Aza-dihydro-acridone derivatives

ABSTRACT

Aza-dihydro-acridone derivatives of formula I, wherein the meaning of R 1 , R′ 1 , R 2  and R 3  is that specified in the description, to be used as T cells proliferation inhibitors.

The present invention relates to aza-dihydro-acridone derivatives offormula I useful for the treatment and/or prevention of an autoimmunedisease, a mast-cell mediated allergy, a rejection of an allotransplantor a xenotransplant of an organ or a tissue, a lymphoma or a T-cellleukaemia, through the inhibition of T cells. Moreover, the inventionrelates to processes for the preparation thereof, and to pharmaceuticalcompositions that comprise these compounds.

STATE OF THE ART

T cells are directly involved in the pathogenesis of autoimmune diseases(ADs), allergies, and diseases associated with abnormal performance ofthe immune system. T cells require three signals for their activation totake place, signal 1, derived from the T cell antigen receptors (TCR);signal 2, derived from co-stimulatory receptors, e.g. CD28 upon bindingto its ligands on the antigen-presenting cells (APC); and signal 3, asignal derived from cytokine receptors responsible for T cellproliferation and differentiation. The mechanism of action of thecurrently-used immunosuppressant drugs based on the inhibition of theactivation of signals 2 or 3, and include drugs such as belatacept andbasiliximab, reslizumab, etc., respectively. The drawback of acting onsignals 2 and 3 is that these signals are not limited to the activationof T cells. This means that currently-used immunosuppressant drugs donot inhibit T cells in a specific manner, and thereof, present hightoxicity. In contrast the TCR signal is limited to T cells. The T cellrecognizes antigen peptides associated to the major histocompatibilitycomplex, also known as MHC, (pMHC) through TCR. The TCR is formed by 6subunits, 2 of which, namely TCRα and TCRβ, are responsible for therecognition of the antigen peptide associated MHC; whereas the other 4subunits (i.e. CD3γ, CD3δ, CD3ε and CD3ζ) are responsible for thetransmission of signals to the T cell cytoplasm. One of the initialprocesses that takes place following ligation of the TCR by the MHC isactivation of the src-family tyrosine kinases, Lck and Fyn, whichphosphorylate the tyrosines in the immunoreceptor tyrosine-basedactivation motifs (ITAM) of the CD3 subunits. These, in turn, becomeanchor sites for the Syk-family tyrosine kinases (ZAP70 and Syk). Inaddition, the TCR undergoes a conformational change that results in thedirect recruitment of the Nck adaptor to a proline-rich sequence (PRS)of the CD3ε subunit. This TCR-Nck interaction takes place between thePRS portion of CD3ε and the amino-terminal SH3.1 domain of Nck.Therefore, Nck is necessary for the activation of T lymphocytes inresponse to stimulation of the TCR. The compounds of the presentinvention surprisingly act blocking the TCR-Nck interaction, andconsequently the abnormal proliferation of T cells.

Autoimmune diseases and diseases associated with abnormal performance ofthe immune system, in general, such as mast-cells mediates allergies,lymphomas, and rejection of allotransplants, are a diverse group ofdiseases whereby the adaptive immune system (in particular, through Tcells) attacks the body's antigens. These diseases are extremelyrelevant, both from the social and the economic standpoint. The lateststatistics indicate that between 3 and 5% of the population suffers fromautoimmune diseases. This incidence, and the chronic nature of thesediseases, represents a high cost for health systems.

State of the art document JPS5714590 discloses aza-dihydro-acridonederivatives. This document further states that said compounds can beused for their analgesic, anti-inflammatory, and antihistamineproperties. However, this document does not provide any effective datasupporting said properties. JP S5714590 would be a non-enablingdisclosure due to the lack of supporting data.

Therefore, there is a need in the field to provide new compounds capableof blocking the TCR-Nck interaction, and consequently capable ofinhibiting T cells abnormal activation/proliferation.

DESCRIPTION OF THE INVENTION

All terms as used herein, unless otherwise provided, shall be understoodin their ordinary meaning as known in the art. Other more specificdefinitions for certain terms as used in the present application are asset forth below and are intended to apply uniformly throughout thedescription and claims unless an otherwise expressly set out definitionprovides a broader one.

A first aspect of the present invention relates to a compound of formulaI:

or a pharmarentically acceptable salt thereof wherein:

----- represents an optional double bond;

each R₁ independently represents —H, —CN, halogen, —OR₄ or —C₁₋₄ alkyl;

each R′₁ independently represents —H, —CN, halogen, —OR₄ or —C₁₋₄ alkyl;

R₂ represents ═O or —OH;

R₃ represents —H, —OR₄, —C₁₋₄ alkyl or C₁₋₄ alkyl-Cy;

Cy represents a phenyl group, a 5- or 6-membered aromatic heterocyclecontaining 1 or 2 heteroatoms selected from O, N and S at any availableposition on the ring, wherein Cy is optionally substituted with one ormore R₄ groups; and

each R₄ group independently represents —H or —C₁₋₄ alkyl;

with the condition that the compound of formula I is not2-benzyl-5-methyl-1,2,3,4-tetrahydro(5H,10OH)-benzo(b)-1,6-naphthyridin-10-one.

In a particular embodiment, the invention relates to the compound offormula I, or a pharmaceutical acceptable salt thereof, as previouslydefined, wherein R₃ represents —H, —C₁₋₄ alkyl or C₁₋₄ alkyl-Cy.

In another particular embodiment, the invention relates to a compound offormula I, or a pharmaceutically acceptable salt thereof, as previouslydefined, selected from a compound of formula Ia:

wherein:

each R₁ independently represents —H, CN, halogen, —OR₄ or —C₁₋₄ alkyl;

each R′₁ independently represents —H, —CN, halogen, —OR₄ or —C₁₋₄ alkyl;

R₂ represents ═O or —OH;

R₃ represents —H, —OR₄, —C₁₋₄ alkyl or —C₁₋₄ alkyl-Cy;

Cy represents a phenyl group, a 5- or 6-membered aromatic heterocyclecontaining 1 or 2 heteroatoms selected from O, N and S at any availableposition on the ring, wherein Cy is optionally substituted with one ormore R₄ groups; and

each R₄ group independently represents —H or —C₁₋₄ alkyl.

In a particular embodiment, the invention relates to a compound offormula Ia, or a pharmaceutically acceptable salt thereof, as previouslydefined, wherein R₃ represents —H, C₁₋₄ alkyl or C₁₋₄ alkyl-Cy.

In another particular embodiment, the invention relates to a compound offormula I, or a pharmaceutically acceptable salt thereof, as previouslydefined, selected from a compound of formula Ib:

wherein:

each R₁ independently represents —H, —CN, halogen, —OR₄ or —C₁₋₄ alkyl;

each R′₁ independently represents —H, —CN, halogen, —OR₄ or —C₁₋₄ alkyl;

R₂ represents ∇O or —OH;

R₃ represents —H, —OR₄, —C₁₋₄ alkyl or —C₁₋₄ alkyl-Cy;

Cy represents a phenyl group, a 5- or 6-membered aromatic heterocyclecontaining 1 or 2 heteroatoms selected from O, N and S at any availableposition on the ring, wherein Cy is optionally substituted with one ormore independent R₄ groups; and

each R₄ group independently represents —H or —C₁₋₄ alkyl;

with the condition that the compound of formula I is not2-benzyl-5-methyl-1,2,3,4-tetrahydro(5H,10H)-benzo(b)-1,6-naphthyridin-10-one.

In a particular embodiment, the invention relates to a compound offormula Ib, or a pharmaceutically acceptable salt thereof, as previouslydefined, wherein R₃ represents —H, —C₁₋₄ alkyl or —C₁₋₄ alkyl-Cy.

In another particular embodiment, the invention relates to a compound offormula Ib, or a pharmaceutically acceptable salt thereof, as previouslydefined, wherein R₁ and R′₁ represent —H, R₂ represents ═O, and R₃represents C₂₋₄ alkyl.

In a particular embodiment, the invention relates to a compound offormula I, Ia or Ib, or a pharmaceutically acceptable salt thereof, aspreviously defined, wherein one R′₁ represents —H, and the other R′₁represents —H, —CN, halogen, —OC₁₋₄ alkyl or C₁₋₄ alkyl.

In another particular embodiment, the invention relates to a compound offormula I, Ia or Ib, or a pharmaceutically acceptable salt thereof, aspreviously defined, wherein both R′₁ represent —H, halogen, —OC₁₋₄ alkylor C₁₋₄ alkyl.

In another particular embodiment, the invention relates to a compound offormula I, Ia or Ib, or a pharmaceutically acceptable salt thereof, aspreviously defined, wherein one R₁ represents —H, and the other R₁represents —H, —CN, halogen, —OC₁₋₄ alkyl or C₁₋₄ alkyl.

In another particular embodiment, the invention relates to a compound offormula I, Ia or Ib, or a pharmaceutically acceptable salt thereof, aspreviously defined, wherein both R₁ represent —H, halogen, —O C₁₋₄ alkylor C₁₋₄ alkyl.

In a particular embodiment, the invention relates to a compound offormula I, Ia or Ib, or a pharmaceutically acceptable salt thereof, aspreviously defined, wherein R₂ represents ═O.

In another particular embodiment, the invention relates to a compound offormula I, Ia or Ib, or a pharmaceutically acceptable salt thereof, aspreviously defined, wherein R₂ represents —OH.

In another particular embodiment, the invention relates to a compound offormula I, Ia or Ib, or a pharmaceutically acceptable salt thereof, aspreviously defined, wherein R₃ represents —H, methyl, ethyl, isopropylor —CH₂-phenyl.

In a particular embodiment, the invention relates to a compound offormula I, or a pharmaceutically acceptable salt thereof, as previouslydefined, selected from:

Another aspect of the present invention relates to a pharmaceuticalcomposition that comprises a compound of formula I, Ia or Ib, or apharmaceutically acceptable salt thereof, as previously defied, and oneor more pharmaceutically acceptable excipients.

Another aspect of the present invention relates to a compound of formulaI, Ia or Ib, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition, as previously defined, for use as amedicament.

In a particular embodiment, the invention relates to a compound offormula I, Ia or Ib, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition, for use as a medicament, as previouslydefined, for the treatment and/or prevention of a disease associatedwith an abnormal activation of T cells.

In a particular embodiment, the invention relates to a compound offormula I, Ia or Ib, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition, for use as previously defined, wherein thedisease associated with an abnormal activation of T cells is selectedfrom the group consisting of: an autoimmune disease, a mast-cellmediated allergy, a rejection of an allotransplant or a xenotransplantof an organ or a tissue, a lymphoma or a T-cell leukaemia.

In another embodiment, the invention relates to a compound of formula IIa or Ib, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition, for use as previously defined, wherein theautoimmune disease is selected from the group consisting of: rheumatoidarthritis, vitiligo, autoimmune hepatitis myasthenia gravis, ankylosingspondylitis, inflammatory bowel disease, Chron's disease, ulcerativecolitis, psoriatic arthritis, transplant rejection, psoriasis, type Idiabetes, multiple sclerosis, systemic lupus erythematosus, asthma andatopic dermatitis.

Alternatively, the invention relates to the use of a compound of formulaI, Ia or Ib, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition, as defined above, for the preparation ormanufacture of a medicament. Alternatively, the invention relates to theuse of a compound of formula I, Ia or Ib, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition, for thepreparation or manufacture of a medicament for the treatment and/orprevention of a disease associated with an abnormal activation of Tcells. Alternatively, the invention relates to a method for thetreatment and/or prevention of a disease associated with abnormalactivation of T cells comprising administering a compound of formula I,Ia or Ib, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition, as defined above.

Another aspect of the present invention relates to a process forpreparing a compound of formula I, I a or Ib, as previously described,which comprises making1,2,3,4-tetrahydro-2-benzo[b][1,6]naphthyridin-10(5H)-one derivativesreact with corresponding substituted benzyl halides under basicconditions.

In the present invention, the term C₁₋₄ alkyl, as a group or a part of agroup, means a linear- or branched-chain alkyl group containing between1 and 4 C atoms, and includes the methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl and tert-butyl groups, wherein the C₁₋₄ alkylmay be substituted or not. If substituents are present, saidsubstituents may be identical or different, and may be located at anyavailable position.

The expression “optionally substituted with one or more” means thepossibility of a group being substituted with one or more substituents.In a particular embodiment, with 1, 2, 3 or 4, substituents. In anotherparticular embodiment with 1, 2 or 3 substituents. In another particularembodiment, with 1 or 2 substituents, provided that said group hassufficient available positions susceptible to being substituted. If theyare present, said substituents may be identical or different, and may belocated at any available position.

Throughout the present description, the terms “treatment” and “treating”refers to the elimination, reduction or decrease of the cause or theeffects of a disease. For purposes of this invention, these termsinclude, without being limited thereto, alleviating, reducing oreliminating one or more symptoms of the disease; reducing the grade ofthe disease, stabilizing (i.e. not worsening) the state of the disease,delaying or slowing the progression of the disease, alleviating orimproving the state of the disease, and remission (whether total orpartial).

As used in the present invention, the terms “prevention”, “preventing”and “prevent” refer to the administration of a compound or apharmaceutical composition according to the invention to a subject whohas not been diagnosed as possibly having the disease at the time of theadministration. Prevention also includes avoiding the reappearance ofthe disease in a subject who has previously suffered said disease. Theprevention may be complete or partial.

The term “subject” or “individual” or “animal” or “patient” includes anysubject, particularly a mammalian subject, for whom therapy is desired.Mammalian subjects include humans, domestic animals, farm animals, andzoo or pet animals. In a particular embodiment of the invention, thesubject is a mammal. In a more particular embodiment of the invention,the subject is a human, preferably a human of any race and sex.

In another embodiment, the invention relates to the compounds of formulaI, Ia of T cells proliferation in a T cells inhibition assay such as theone described in the activity example.

The compounds of the present invention contain one or more basicnitrogens and, therefore, may form salts by reacting with acids, bothorganic and inorganic. Examples of said salts include, withoutlimitation: salts of inorganic acids, such as hydrochloric acid,hydrobromic acid, hydriodic acid, nitric acid, perchloric acid, sulfuricacid or phosphoric acid; and salts of organic acids, such asmethanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalicacid, acetic acid, maleic acid, ascorbic acid, citric acid, lactic acid,tartaric acid, malonic acid, glycolic acid, succinic acid and propionicacid, amongst others. Some compounds of the present invention maycontain one or more acidic protons and, therefore, may also form saltsby reacting with bases. Examples of said salts include, withoutlimitation: salts of inorganic cations, such as sodium, potassium,calcium, magnesium, lithium, aluminum, zinc, etc.; and salts formed withpharmaceutically acceptable amines, such as ammonia, alkylamines,hydroxyalkylamines, lysine, arginine, N-methylglucamine, procaine andsimilar ones.

There are no limitations as to the types of salts that may be used,provided that they are pharmaceutically acceptable to be used fortherapeutic purposes. Pharmaceutically acceptable salts are understoodto mean those salts which, according to medical criteria, are adequateto be used in contact with human beings' or other mammals' tissueswithout causing undue toxicity, irritation, allergic responses orsimilar effects. Pharmaceutically acceptable salts are widely known to aperson skilled in the art.

The salts of a compound of formula I, Ia or Ib may be obtained duringthe final isolation and purification of the compounds of the inventionor be prepared by treating a compound of formula I, Ia or Ib with asufficient quantity of the desired acid or base to produce the salt in aconventional manner. The salts of compounds of formula I, Ia or Ib may,in turn, be converted into other salts of compounds of formula I, Ia orIb, respectively, by means of ion-exchange using an ion-exchange resin.

The compounds of formula I, Ia or Ib and the salts thereof may differ interms of certain physical properties, but, for purposes of theinvention, are equivalent. All the salts of compounds of formula I, Iaor Ib are included within the scope of the invention.

The compounds of the present invention may form complexes with solventswith which they are made to react or from which they are precipitated orcrystallized. These complexes are known as solvates. As used herein, theterm “solvate” refers to a complex of and a solvent. Examples ofsolvents include, without limitation, pharmaceutically acceptablesolvents such as water, ethanol and similar ones. A complex formed bywater is known as a hydrate. Solvates of the compounds of the invention(or the salts thereof), including hydrates, are included within thescope of the invention.

The compounds of formula I, Ia or Ib may exist in different physicalforms, i.e. in amorphous form and in crystalline forms. Moreover, thecompounds of the present invention may be capable of crystallizing inmore than one form, a characteristic known as polymorphism. Polymorphsmay differ in terms of some physical properties, which are widely knownto persons skilled in the art, such as, for example, X-raydiffractograms, melting points or solubility. All the physical forms ofthe compounds of formula I, Ia or Ib, including all the polymorphicforms thereof (“polymorphs”), are included within the scope of thepresent invention.

Some compounds of the present invention may exist in the form of severaldiastereoisomers and/or several optical isomers. Diastereoisomers may beseparated by means of conventional techniques, such as fractionalchromatography or crystallization. Optical isomers may be resolved bymeans of conventional optical resolution techniques, to produceoptically pure isomers. This resolution may be performed on chiralsynthesis intermediate compounds or on the products of formula I, Ia orIb. The optically pure isomers may also be individually obtained usingenantiospecifc syntheses. The present invention includes both individualisomers and mixtures thereof (for example, racemic mixtures or mixturesof diastereoisomers), whether obtained by means of synthesis or byphysical mixing.

The present invention also relates to a pharmaceutical composition thatcomprises a compound of the invention (or a pharmaceutically acceptablesalt or solvate thereof) and one or more pharmaceutically acceptableexcipients. The excipients must be “acceptable” in the sense of beingcompatible of remaining ingredients of the composition and not beharmful for those taking said composition.

The compounds of the present invention may be administered in the formof any pharmaceutical formulation, the nature whereof, as is well known,will be dependent on the nature of the active principle and itsadministration route. In principle, any administration route may beused, for example, oral, parenteral, nasal, ocular, rectal, and topical.

Solid compositions for oral administration include tablets, granules andcapsules. In any case, the manufacturing method will be based on simplemixing, dry granulation or wet granulation of the active principle withexcipients. These excipients may be, phosphate; binding agents such as,for example, starch, gelatine or polyvinylpyrrolidone; disaggregatingagents such as sodium carboxymethyl starch or sodium croscarmellose; andlubricating agents such as, for example, magnesium stearate, stearicacid or talc. The tablets may further be coated with adequate excipientsby means of known techniques, in order to delay the disaggregation andabsorption thereof in the gastrointestinal tract, and thus achieve asustained action over a longer period of time, or simply improve theirorganoleptic properties or their stability. The active principle mayalso be incorporated by coating inert pellets using natural or syntheticfilmogenic polymers. It is also possible to manufacture soft gelatinecapsules, wherein the active principle is mixed with water or with anoily medium, such as, for example, coconut oil, liquid paraffin or oliveoil.

Powders and granules may be obtained in order to prepare oralsuspensions by adding water, mixing the active principle with dispersingor wetting agents, suspending agents and preservatives. Other excipientsmay also be added, for example, sweetening, flavoring and coloringagents.

Liquid forms for oral administration may include emulsions, solutions,suspensions, syrups and elixirs that contain commonly used inertdiluents, such as distilled water, ethanol, sorbitol, glycerol,polyethylene glycols (macrogols) and propylene glycol. Said compositionsmay also contain adjuvants, such as wetting, suspending, sweetening andflavoring agents, preservatives and pH regulators.

According the present invention, injectable preparations, for parenteraladministration, comprise sterile solutions, suspensions or emulsions, inan aqueous or non-aqueous solvent, such as propylene glycol,polyethylene glycol or vegetable oils. These compositions may alsocontain adjuvants, such as wetting, emulsifying and dispersing agents,and preservatives. They may be sterilized by means of any commonly knownmethod or prepared as sterile solid compositions that are subsequentlydissolved in water or any other sterile injectable medium immediatelyprior to use. It is also possible to start from sterile raw materialsand keep them under these conditions during the entire manufacturingprocess.

For rectal administration, the active principle may be preferablyformulated as suppositories on oily bases, such as, for example,vegetable oils or semi-synthetic solid glycerides, or on hydrophilicbases, such as polyethylene glycols (macrogols).

The compounds of the invention may also be formulated for topicalapplication, for the treatment of pathologies that affect areas ororgans that are accessible by said route.

These formulations include creams, lotions, gels, powders, solutions andpatches wherein the compound is dispersed or dissolved in adequateexcipients.

For nasal administration or inhalation, the compound may be formulatedin the form of an aerosol, wherefrom it is conveniently released usingadequate propellants.

The appropriate dosage as well as the dosing frequency of the compoundof the invention, or salt thereof, within the pharmaceutical compositionwill depend on the nature of disease to be treated or prevented, theseverity and the course of the disease, the subject's age, gender,general condition and weight, whether the composition is administeredfor preventive or therapeutic purposes, among other factors. The amountof the compound of the invention, or salt thereof, or the pharmaceuticalcomposition is suitably administered to the subject at one time or overa series of treatments. Depending on the type and severity of thedisease, an appropriate dosage level will generally be about 0.01 to1,000 mg per kg patient body weight per day which can be administered insingle or multiple doses. Preferably, the dosage level will be about 0.1to about 500 mg/kg per day; more preferably about 0.25 to about 250mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. Asuitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. For oraladministration, the composition is preferably provided in the form oftablets, containing from about 1.0 to about 1,000 mg of active compound,particularly at least about 1.0, at least about 5.0, at least about10.0, at least about 15.0, at least about 20.0, at least about 25.0, atleast about 50.0, at least about 75.0, at least about 100.0, at leastabout 150.0, at least about 200.0, at least about 250.0, at least about300.0, at least about 400.0, at least about 500.0, at least about 600.0,at least about 750.0, at least about 800.0, at least about 900.0, atleast about 1000.0 mg. The compound, salt thereof, or pharmaceuticalcomposition may be administered on a regime of 1 to 4 times per day,preferably one or twice per day.

The invention also relates to all possible combinations of the aboveaspects and particular embodiments.

Throughout the description and the claims, the word “comprises” andvariants thereof are not intended to exclude other technicalcharacteristics, additives, components or steps. For a person skilled inthe art, other objects, advantages and characteristics of the inventionwill arise, partly from the description and partly from the practice ofthe invention. The following examples and figures are provided forillustrative purposes, and are not intended to limit the scope of thepresent invention.

CERTAIN EMBODIMENTS OF THE INVENTION I. Compounds

In some embodiments, the present invention provides a compound offormula I:

or a pharmaceutically acceptable salt thereof, wherein:

----- represents an optional double bond;

each R₁ independently represents —H, —CN, halogen, —OR₄ or —C₁₋₄ alkyl;

each R′₁ independently represents —H, —CN, halogen, —OR₄ or —C₁₋₄ alkyl;

R₂ represents ═O or —OH;

R₃ represents —H, —OR₄, —C₁₋₄ alkyl or —C₁₋₄ alkyl-Cy;

Cy represents a phenyl group, a 5- or 6-membered aromatic heterocyclecontaining 1 or 2 heteroatoms selected from O, N and S at any availableposition on the ring, wherein Cy is optionally substituted with one ormore R₄ groups; and

each R₄ group independently represents —H or —C₁₋₄ alkyl;

with the condition that the compound of formula I is not2-benzyl-5-methyl-1,2,3,4-tetrahydro(5H,10H)-benzo(b)-1,6-naphthyridin-10-one.

As defined generally above, ----- represents an optional double bond.

In some embodiments, ----- represents a double bond.

In some embodiments, ----- does not represents a double bond.

In some embodiments, ----- is selected from those depicted in Tables 1and 2 below.

As defined generally above, each R₁ independently represents —H, —CN,halogen, —OR₄ or —C₁₋₄ alkyl, wherein R₄ is as described in embodimentsherein.

In some embodiments, R₁ is —H. In some embodiments, R₁ is —CN, halogen,—OR₄ or —C₁₋₄ alkyl, wherein R₄ is as described in embodiments herein.

In some embodiments, R₁ is —CN.

In some embodiments, R₁ is halogen. In some embodiments, R₁ is F. Insome embodiments, R₁ is Cl. In some embodiments, R₁ is Br. In someembodiments, R₁ is I.

In some embodiments, R₁ is —OR₄, wherein R₄ is as described inembodiments herein.

In some embodiments, R₁ is —C₁₋₄ alkyl. In some embodiments, R₁ ismethyl. In some embodiments, R₁ is ethyl. In some embodiments, R₁ ispropyl. In some embodiments, R₁ is isopropyl. In some embodiments, R₁ isbutyl. In some embodiments, R₁ is isobutyl. In some embodiments, R₁ ist-butyl.

In some embodiments, R₁ is selected from those depicted in Tables 1 and2 below.

As defined generally above, each R′₁ independently represents —H, —CN,halogen, —OR₄ or —C₁₋₄ alkyl, wherein R₄ is as described in embodimentsherein.

In some embodiments, R′₁ is —H. In some embodiments, R′₁ is —CN,halogen, —OR₄ or —C₁₋₄ alkyl, wherein R₄ is as described in embodimentsherein.

In some embodiments, R′₁ is —CN.

In some embodiments, R′₁ is halogen. In some embodiments, R′₁ is F. Insome embodiments, R′₁ is Cl. In some embodiments, R′₁ is Br. In someembodiments, R′₁ is I.

In some embodiments, R′₁ is —OR₄, wherein R₄ is as described inembodiments herein.

In some embodiments, R′₁ is —C₁₋₄ alkyl. In some embodiments, R′₁ ismethyl. In some embodiments, R′₁ is ethyl. In some embodiments, R′₁ ispropyl. In some embodiments, R′₁ is isopropyl. In some embodiments, R′₁is butyl. In some embodiments, R′₁ is isobutyl. In some embodiments, R′₁is t-butyl.

In some embodiments, R′₁ is selected from those depicted in Tables 1 and2 below.

As defined generally above, R₂ represents ═O or —OH.

In some embodiments, R₂ is ═O. In some embodiments, R₂ is —OH.

In some embodiments, R₂ is selected from those depicted in Tables 1 and2 below.

As defined generally above, R₃ represents —H, —OR₄, —C₁₋₄ alkyl or —C₁₋₄alkyl-Cy, wherein each of R₄ and Cy is as described in embodimentsherein.

In some embodiments, R₃ is —H. In some embodiments, R₃ is —OR₄, —C₁₋₄alkyl or —C₁₋₄ alkyl-Cy, wherein each of R₄ and Cy is as described inembodiments herein.

In some embodiments, R₃ is —OR₄, wherein R₄ is as described inembodiments herein.

In some embodiments, R₃ is —C₁₋₄ alkyl. In some embodiments, R₃ ismethyl. In some embodiments, R₃ is ethyl. In some embodiments, R₃ ispropyl. In some embodiments, R₃ is isopropyl. In some embodiments, R₃ isbutyl. In some embodiments, R₃ is isobutyl. In some embodiments, R₃ ist-butyl.

In some embodiments, R₃ is —C₁₋₄ alkyl-Cy, wherein Cy is as described inembodiments herein. In some embodiments, R₃ is —CH₂—Cy, wherein Cy is asdescribed in embodiments herein. In some embodiments, R₃ is —(CH₂)₂—Cyor —CH(CH₃)—Cy, wherein Cy is as described in embodiments herein. Insome embodiments, R₃ is —(CH₂)₃—Cy, —CH(CH₃)CH₂—Cy, —CH₂CH(CH₃)—Cy, or—CH(CH₂CH₃)—Cy, wherein Cy is as described in embodiments herein. Insome embodiments, R₃ is —(CH₂)₄—Cy, —CH(CH₃)CH₂CH₂—Cy,—CH₂CH(CH₃)CH₂—Cy, —CH₂CH₂CH(CH₃)—Cy, —CH(CH₂CH₃)CH₂—Cy,—CH₂CH(CH₂CH₃)—Cy, —CH(CH₂CH₂CH₃)—Cy, or —CH(CH(CH₃)₂)—Cy, wherein Cy isas described in embodiments herein.

In some embodiments, R₃ is selected from those depicted in Tables 1 and2 below.

As defined generally above, Cy represents a phenyl group, a 5- or6-membered aromatic heterocycle containing 1 or 2 heteroatoms selectedfrom O, N and S at any available position on the ring, wherein Cy isoptionally substituted with one or more R₄ groups, and wherein each R₄is independently as described in embodiments herein.

In some embodiments, Cy is phenyl, optionally substituted with one ormore R₄ groups, wherein each R₄ is independently as described inembodiments herein. In some embodiments, Cy is phenyl, optionallysubstituted with one R₄ group, wherein R₄ is as described in embodimentsherein. In some embodiments, Cy is phenyl, optionally substituted withtwo R₄ groups, wherein each of R₄ is independently as described inembodiments herein. In some embodiments, Cy is phenyl, optionallysubstituted with three R₄ groups, wherein each of R₄ is independently asdescribed in embodiments herein. In some embodiments, Cy is phenyl,optionally substituted with four R₄ groups, wherein each of R₄ isindependently as described in embodiments herein. In some embodiments,Cy is phenyl, optionally substituted with five R₄ groups, wherein eachof R₄ is independently as described in embodiments herein.

In some embodiments, Cy is a 5-membered aromatic heterocycle containing1 heteroatom selected from O, N and S at any available position on thering, wherein Cy is optionally substituted with one or more R₄ groups,and wherein each R₄ is independently as described in embodiments herein.In some embodiments, Cy is a 5-membered aromatic the ring, wherein Cy isoptionally substituted with one or more R₄ groups, and wherein each R₄is independently as described in embodiments herein.

In some embodiments, Cy is a 6-membered aromatic heterocycle containing1 heteroatom selected from O, N and S at any available position on thering, wherein Cy is optionally substituted with one or more R₄ groups,and wherein each R₄ is independently as described in embodiments herein.In some embodiments, Cy is a 6-membered aromatic heterocycle containing2 heteroatoms selected from O, N and S at any available position on thering, wherein Cy is optionally substituted with one or more R₄ groups,and wherein each R₄ is independently as described in embodiments herein.

In some embodiments, Cy is selected from those depicted in Tables 1 and2 below.

As defined generally above, each R₄ group independently represents —H or—C₁₋₄ alkyl.

In some embodiments, R₄ is —H.

In some embodiments, R₄ is —C₁₋₄ alkyl. In some embodiments, R₄ ismethyl. In some embodiments, R₄ is ethyl. In some embodiments, R₄ ispropyl. In some embodiments, R₄ is isopropyl. In some embodiments, R₄ isbutyl. In some embodiments, R₄ is isobutyl. In some embodiments, R₄ ist-butyl.

In some embodiments, each of R₄ is independently selected from thosedepicted in Tables 1 and 2 below.

In some embodiments, the present invention provides to a compound offormula Ia:

or a pharmaceutically acceptable salt thereof, wherein each of R₁, R′₁,R₂, R₃, Cy and R₄ is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides to a compound offormula Ib:

or a pharmaceutically acceptable salt thereof, wherein each of R₁, R′₁,R₂, R₃, Cy and R₄ is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound selectedfrom Tables 1 and 2.

TABLE 1 Exemplary compounds

Ia-1

Ia-2

Ia-3

Ia-4

TABLE 2 Exemplary compounds

Ib-1

Ib-2

Ib-3

Ib-4

Ib-5

Ib-6

Ib-7

Ib-8

Ib-9

Ib-10

Ib-11

Ib-12

Ib-13

Ib-14

Ib-15

Ib-16

Ib-17

Ib-18

Ib-19

Ib-20

Ib-21

Ib-22

Ib-23

Ib-24

Ib-25

Ib-26

Ib-27

Ib-28

Ib-29

Ib-30

The compounds of this invention may be prepared or isolated in generalby synthetic and/or semi-synthetic methods known to those skilled in theart for analogous compounds and by methods described in detail in theExamples, herein.

In some embodiments, the present invention provides a method forpreparing a compound of formula I, or a salt thereof, comprisingreacting a compound of formula II:

or a salt thereof, with a compound of formula III:

or a salt thereof, wherein LG is a leaving group, and each of R₁, R′₁,R₂, R₃, Cy and R₄ is as defined above and described in embodimentsherein, both singly and in combination.

Examples of leaving groups (“LG”) are described in detail in, forexample, March's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, M. B. Smith and J. March, 5th Edition, John Wiley & Sons,2001, Comprehensive Organic Transformations, R. C. Larock, 2^(nd)Edition, John Wiley & Sons, 1999, and Protecting Groups in OrganicSynthesis, T. W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley &Sons, 1999, the entirety of each of which is hereby incorporated hereinby reference.

A leaving group (“LG”) can be, but is not limited to, halogens (e.g.fluoride, chloride, bromide, iodide), sulfonates (e.g. mesylate,tosylate, benzenesulfonate, brosylate, nosylate, triflate), diazonium,and the like.

In some embodiments, a leaving group (“LG”) is halogen. In someembodiments, a leaving group (“LG”) is F. In some embodiments, a leavinggroup (“LG”) is Cl. In some embodiments, a leaving group (“LG”) is Br.In some embodiments, a leaving group (“LG”) is I.

In some embodiments, a leaving group (“LG”) is a sulfonate group. Insome embodiments, a leaving group (“LG”) is a mesylate group. In someembodiments, a leaving group (“LG”) is a tosylate group. In someembodiments, a leaving group (“LG”) is a benzenesulfonate group. In someembodiments, a leaving group (“LG”) is a brosylate group. In someembodiments, a leaving group (“LG”) is a nosylate group. In someembodiments, a leaving group (“LG”) is a triflate group.

In some embodiments, a compound of formula II, or a salt thereof, is acompound of formula IIa:

or a salt thereof, wherein each of R₁, R₂, R₃, Cy and R₄ is as definedabove and described in embodiments herein, both singly and incombination.

In some embodiments, a compound of formula II, or a salt thereof, is acompound of formula IIb:

or a salt thereof, wherein each of R₁, R₂, R₃, Cy and R₄ is as definedabove and described in embodiments herein, both singly and incombination.

In some embodiments, the compounds of the present invention of FormulaI, or subformulae thereof, or a salt thereof, are generally preparedaccording to the schemes set forth in the examples.

II. Pharmaceutically Acceptable Composition

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier, adjuvant, orvehicle. The amount of compound in compositions of this invention issuch that is effective to measurably modulate the interaction betweenTCR and Nck, in a biological sample or in a patient. In certainembodiments, the amount of compound in compositions of this invention issuch that is effective to measurably modulate the interaction betweenTCR and Nck in a biological sample or in a patient. In certainembodiments, a composition of this invention is formulated foradministration to a patient in need of such composition. In someembodiments, a composition of this invention is formulated for oraladministration to a patient.

In some embodiments, the invention provides a pharmaceutical compositioncomprising the compound:

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.

The term “patient,” as used herein, means an animal, preferably amammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants, or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts, orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

Compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see supra) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, provided pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of compounds of this inventioninclude, but are not limited to, mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. Alternatively, providedpharmaceutically acceptable compositions can be formulated in a suitablelotion or cream containing the active components suspended or dissolvedin one or more pharmaceutically acceptable carriers. Suitable carriersinclude, but are not limited to, mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay as solutions in isotonic, pH adjusted sterile saline, either with orwithout a preservative such as benzylalkonium chloride. Alternatively,for ophthalmic uses, the pharmaceutically acceptable compositions may beformulated in an ointment such as petrolatum.

Pharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that may be combinedwith the carrier materials to produce a composition in a single dosageform will vary depending upon the host treated, the particular mode ofadministration. Preferably, provided compositions should be formulatedso that a dosage of between 0.01-100 mg/kg body weight/day of theinhibitor can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

Pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracistemally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can poly(anhydrides). Depot injectableformulations are also prepared by entrapping the compound in liposomesor microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar—agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well-known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and coatings and other coatings well-known inthe pharmaceutical formulating art. In such solid dosage forms theactive compound may be admixed with at least one inert diluent such assucrose, lactose or starch. Such dosage forms may also comprise, as isnormal practice, additional substances other than inert diluents, e.g.,tableting lubricants and other tableting aids such a magnesium stearateand microcrystalline cellulose. In the case of capsules, tablets andpills, the dosage forms may also comprise buffering agents. They mayoptionally contain opacifying agents and can also be of a compositionthat they release the active ingredient(s) only, or preferentially, in acertain part of the intestinal tract, optionally, in a delayed manner.Examples of embedding compositions that can be used include polymericsubstances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof biopsied material obtainedfrom a mammal or extracts thereof and blood, saliva, urine, feces,semen, tears, or other body fluids or extracts thereof.

III. Uses of Compounds and Pharmaceutically Acceptable Compositions

Compounds and compositions described herein are generally useful for themodulation of TCR signaling and T-cell activation via modulation of theinteraction between TCR and Nck.

The activity of a compound utilized in this invention as a modulator ofthe TCR-Nck interaction, may be assayed in vitro, in vivo or in a cellline. In vitro assays include, for example, assays that measure theproliferation of T-lymphocytes (e.g., Tse, W. T. et al.,Transplantation, 2003, 75(3): 389-97, whose contents is incorporatedherein in its entirety by stimulation (e.g., Fuller, C. L. et al.,Immunol. Rev. 2003, 292: 220-36, whose contents is incorporated hereinin its entirety by reference); and measure the secretion of cytokines byT-cells caused by stimulation of the TCR (e.g., Finco, D. et al.,Cytokine, 2014, 66(2): 143-55, whose contents is incorporated herein inits entirety by reference). In vivo assays include standard animalmodels for immune and autoimmune disease, which are well-known and arepart of the state of the art such as, for example, delayedhypersensitivity (e.g., Kudlacz, E. et al., Am. J. Transplant., 2004,4(1): 51-7, whose contents is incorporated herein in its entirety byreference); models for rheumatoid arthritis (e.g., Holmdahl, R. et al.,APMIS, 1989, 97(7): 575-84, whose contents is incorporated herein in itsentirety by reference); models of multiple sclerosis (experimentalautoimmune encephalomyelitis) (e.g., Gonzalez-Rey, E. et al., Am. J.Pathol. 2006, 168(4): 1179-88, whose contents is incorporated herein inits entirety by reference; and models of transplant rejection (see,e.g., various animal models described in the references above inrelation to the treatment of transplant rejection, incorporated here byreference).

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment may be administeredafter one or more symptoms have developed. In other embodiments,treatment may be administered in the absence of symptoms. For example,treatment may be administered to a susceptible individual prior to theonset of symptoms (e.g., in light of a history of symptoms and/or inlight of genetic or other susceptibility factors). Treatment may also becontinued after symptoms have resolved, for example to prevent or delaytheir recurrence.

Provided compounds are modulators of the TCR-Nck interaction and aretherefore useful for treating one or more disorders associated withactivity of TCR. Thus, in certain embodiments, the present inventionprovides a method for treating a TCR-Nck mediated disorder comprisingthe step of administering to a patient in need thereof a compound of thepresent invention, or pharmaceutically acceptable composition thereof.

As used herein, the terms “TCR-Nck mediated” disorders, diseases, and/orconditions means any disease, or other deleterious condition, in whichthe TCR is known to play a role. Accordingly, another embodiment of thepresent invention relates to treating or lessening the severity of oneor more diseases in which TCR is known to play a role. Such TCT-Nckmediated disorders include, without limitation, autoimmune andinflammatory disorders; disorders associated with transplantation;proliferative disorders; and neurological Cvrlje, M. et al., Curr.Pharm. Des. 2004, 10(15): 1767-84; Cetkovic-Cvrlje, M. et al., Arch.Immunol. Ther. Exp. 2004, 52(2): 69-82).

In some embodiments, the present invention provides a method fortreating a disorder mediated by TCR-Nck interaction in a patient in needthereof, comprising the step of administering to said patient a compoundaccording to the present invention or pharmaceutically acceptablecomposition thereof. In some embodiments, the method of modulatingTCR-Nck is used to treat autoimmune and inflammatory disorders;disorders associated with transplantation; proliferative disorders; andneurological disorders. In some embodiments, an autoimmune andinflammatory disorder, a disorder associated with transplantation, aproliferative disorder, and a neurological disorder is selected from thedisease/disorder as described herein.

In some embodiments, the method of modulating TCR-Nck is used to treatalopecia areata. (See, e.g., Petukhova, L. et al., Nature, 2010,466(7302): 113-17). Accordingly, in some embodiments, the presentinvention provides a method of treating alopecia areata, in a patient inneed thereof, comprising the step of administering to said patient aprovided compound or a pharmaceutically acceptable salt thereof.

In some embodiments, the method of modulating TCR-Nck is used to treatankylosing spondylitis. (See, e.g., Smith, J. A., Curr Allergy AsthmaRep. 2015, 15(1): 489). Accordingly, in some embodiments, the presentinvention provides a method of treating ankylosing spondylitis, in apatient in need thereof, comprising the step of administering to saidpatient a provided compound or a pharmaceutically acceptable saltthereof.

In some embodiments, the method of modulating TCR-Nck is used to treatasthma. (See, e.g., Robinson, D. S., J. Allergy Clin. Immunol., 2010,126(6): 1081-91). Accordingly, in some embodiments, the presentinvention provides a method of treating asthma, in a patient in needthereof, comprising the step of administering to said patient a providedcompound or a pharmaceutically acceptable salt thereof.

In some embodiments, the method of modulating TCR-Nck is used to treatautoimmune hepatitis. (See, e.g., Manns, M. P. et al., Hepatology, 2010,51(6), 2193-213. Accordingly, in some embodiments, the present inventionprovides a method of treating autoimmune hepatitis, in a patient in needthereof, comprising the step of administering to said patient a providedcompound or a pharmaceutically acceptable salt thereof.

In some embodiments, the method of modulating TCR-Nck is used to treatautoimmune lymphoproliferative syndrome (ALPS). (See, e.g., Sneller, M.C. et al., Curr. Opin. invention provides a method of treating ALPS, ina patient in need thereof, comprising the step of administering to saidpatient a provided compound or a pharmaceutically acceptable saltthereof.

In some embodiments, the method of modulating TCR-Nck is used toautoimmune myocarditis. (See, e.g., Caforio, A. L. and Iliceto, S.,Curr. Opin. Cardiol., 2008, 23(3): 219-26). Accordingly, in someembodiments, the present invention provides a method of treatingautoimmune myocarditis, in a patient in need thereof, comprising thestep of administering to said patient a provided compound or apharmaceutically acceptable salt thereof.

In some embodiments, the method of modulating TCR-Nck is used toautoimmune orchitis. (See, e.g., Silva, C. A. et al., Autoimmun Rev.,2014, 13(4-5): 431-34). Accordingly, in some embodiments, the presentinvention provides a method of treating autoimmune orchitis, in apatient in need thereof, comprising the step of administering to saidpatient a provided compound or a pharmaceutically acceptable saltthereof.

In some embodiments, the method of modulating TCR-Nck is used toautoimmune pancreatitis. (See, e.g., Fan, B. G. and Andren-Sandberg, A.,N. Am. J. Med. Sci. 2009, 1(2): 148-51). Accordingly, in someembodiments, the present invention provides a method of treatingautoimmune pancreatitis, in a patient in need thereof, comprising thestep of administering to said patient a provided compound or apharmaceutically acceptable salt thereof.

In some embodiments, the method of modulating TCR-Nck is used to treatatopic dermatitis. (See, e.g., Nograles, K. E. et al., J. Allergy Clin.Immunol., 2009, 123(6): 1244-52). Accordingly, in some embodiments, thepresent invention provides a method of treating systemic atopicdermatitis, in a patient in need thereof, comprising the step ofadministering to said patient a provided compound or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the method of modulating TCR-Nck is used to treatBehçet's disease. (See, e.g., Direskeneli, H., Genetics ResearchInternational, 2013, Article ID 249157 doi:10.1155/2013/249157).Accordingly, in some embodiments, the present invention provides amethod of treating Behçet's disease, in a patient in need thereof,comprising the step of administering to said patient a provided compoundor a pharmaceutically acceptable salt thereof.

In some embodiments, the method of modulating TCR-Nck is used to treatAccordingly, in some embodiments, the present invention provides amethod of treating Castleman disease, in a patient in need thereof,comprising the step of administering to said patient a provided compoundor a pharmaceutically acceptable salt thereof.

In some embodiments, the method of modulating TCR-Nck is used to treatCeliac disease. (See, e.g., Mazzarella, G., World J. Gastroenterol.,2015, 21(24): 7349-56). Accordingly, in some embodiments, the presentinvention provides a method of treating Celiac disease, in a patient inneed thereof, comprising the step of administering to said patient aprovided compound or a pharmaceutically acceptable salt thereof.

In some embodiments, the method of modulating TCR-Nck is used to treatchronic inflammatory demyelinating polyneuropathy. (See, e.g., Notturno,F. et al., J. Neuroimmunol. 2008, 197(2): 124-7). Accordingly, in someembodiments, the present invention provides a method of treating chronicinflammatory demyelinating polyneuropathy, in a patient in need thereof,comprising the step of administering to said patient a provided compoundor a pharmaceutically acceptable salt thereof.

In some embodiments, the method of modulating TCR-Nck is used to treatCogan's syndrome. (See, e.g., Greco, A. et al., Autoimmunity Rev. 2013,12(3): 396-400). Accordingly, in some embodiments, the present inventionprovides a method of treating Cogan's syndrome, in a patient in needthereof, comprising the step of administering to said patient a providedcompound or a pharmaceutically acceptable salt thereof.

In some embodiments, the method of modulating TCR-Nck is used to treatChurg-Strauss syndrome. (See, e.g., Guida, G. et al., Clin. Immunol.,2008 128(1): 94-102). Accordingly, in some embodiments, the presentinvention provides a method of treating Churg-Strauss syndrome, in apatient in need thereof, comprising the step of administering to saidpatient a provided compound or a pharmaceutically acceptable saltthereof.

In some embodiments, the method of modulating TCR-Nck is used to treatCrohn's disease. (See, e.g., Roche, J. K. et al., J. Clin. Invest. 1985,75(2):522-530; Marks, D. J. and Segal, A. W. J. Pathol. 2008, 214(2):260-66; Cobrin, G. M. and Abreu, M. T. Immunol. Rev. 2005, 206(1):277-95). Accordingly, in some embodiments, the present inventionprovides a method of treating Crohn's disease, in a patient in needthereof, comprising the step of administering to said patient a providedcompound or a pharmaceutically acceptable salt thereof.

In some embodiments, the method of modulating TCR-Nck is used to treatEvans syndrome. (See, e.g., Teachery, D. T. et al., Blood, 2004,105(6):2443-48). Accordingly, a patient in need thereof, comprising thestep of administering to said patient a provided compound or apharmaceutically acceptable salt thereof.

In some embodiments, the method of modulating TCR-Nck is used to treatinclusion body myositis. (See, e.g., Kitazawa, M. et al., J.Neuroscience, 2009, 29(19): 6132-41). Accordingly, in some embodiments,the present invention provides a method of treating inclusion bodymyositis, in a patient in need thereof, comprising the step ofadministering to said patient a provided compound or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the method of modulating TCR-Nck is used to treatinflammatory bowel disease. (See, e.g., Zenewicz, L. A. et al., TrendsMol. Med., 2009, 15(5): 199-207). Accordingly, in some embodiments, thepresent invention provides a method of treating inflammatory boweldisease, in a patient in need thereof, comprising the step ofadministering to said patient a provided compound or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the method of modulating TCR-Nck is used to treatKawasaki disease. (See, e.g., Onouchi, Y. et al., Nature Genetics, 2008,40: 35-42). Accordingly, in some embodiments, the present inventionprovides a method of treating Kawasaki disease, in a patient in needthereof, comprising the step of administering to said patient a providedcompound or a pharmaceutically acceptable salt thereof.

In some embodiments, the method of modulating TCR-Nck is used to treatLyme disease (chronic). (See, e.g., Singh, S. K. and Girschick, H. J.Paediatric Rheumatology, 2004, 10(7): 598-614; Raveche, E. S. et al., J.Clin. Microbiol. 2005, 43(2): 850-56). Accordingly, in some embodiments,the present invention provides a method of treating Lyme disease(chronic), in a patient in need thereof, comprising the step ofadministering to said patient a provided compound or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the method of modulating TCR-Nck is used to treatmultiple sclerosis. (See, e.g., Babbe, H. et al., J. Exp. Med., 2000,192(3): 393-404; Dai, K. Z. et al., Genes Immun. 2001, 2(5): 263-8).Accordingly, in some embodiments, the present invention provides amethod of treating multiple sclerosis, in a patient in need thereof,comprising the step of administering to said patient a provided compoundor a pharmaceutically acceptable salt thereof.

In some embodiments, the method of modulating TCR-Nck is used to treatmyasthenia gravis. (See, e.g., Meriggioli, M. N. and Sanders, D. B. S.,Lancet Neurology, 2009, 8(5): 475-90). Accordingly, in some embodiments,the present invention provides a method of treating myasthenia gravis,in a patient in need thereof, comprising the step of administering tosaid patient a provided compound or a pharmaceutically acceptable saltthereof.

In some embodiments, the method of modulating TCR-Nck is used to treatpsoriasis. (See, e.g., Cai, Y. et al., Cell Mol. Immunol., 2012, 9(4):302-09). Accordingly, in some embodiments, the present inventionprovides a method of treating psoriasis, in a patient in need thereof,comprising the step of administering to said patient a provided compoundor a pharmaceutically acceptable salt thereof.

In some embodiments, the method of modulating TCR-Nck is used to treatpsoriatic arthritis. (See, e.g., Choy, E., Curr. Rheumatol. Rep. Exp.,2007, 9(6): 437-41). Accordingly, in some embodiments, the presentinvention provides a method of treating psoriatic arthritis, in apatient in need thereof, comprising the step of administering to saidpatient a provided compound or a pharmaceutically acceptable saltthereof.

In some embodiments, the method of modulating TCR-Nck is used to treatrheumatoid arthritis. (See, e.g., Cope, A. P. et al., Clin. Exp.Rheumatol., 2007, 25(5): S4-11). Accordingly, in some embodiments, thepresent invention provides a method of treating rheumatoid arthritis, ina patient in need thereof, comprising the step of administering to saidpatient a provided compound or a pharmaceutically acceptable saltthereof.

In some embodiments, the method of modulating TCR-Nck is used to treatsystemic lupus erythematosus. (See, e.g., Crispin, J. C. et al., J.Immunol., 2008, 181(12): 8761-66; Linterman, M. A. et al., J. Exp. Med.2009, 206(3): 561-76). Accordingly, in some embodiments, the presentinvention provides a method of treating systemic lupus erythematosus, ina patient in need thereof, comprising the step of administering to saidpatient a provided compound or a pharmaceutically acceptable saltthereof.

In some embodiments, the method of modulating TCR-Nck is used to treattype I diabetes. (See, e.g., Roep, B. O., Diabetologia, 46(3): 305-21).Accordingly, in some embodiments, the present invention provides amethod of treating type I diabetes, in a patient in need thereof,comprising the step of administering to said patient a provided compoundor a pharmaceutically acceptable salt thereof.

In some embodiments, the method of modulating TCR-Nck is used to treatulcerative colitis. (See, e.g., Kappeler, A. and Mueller, C., HistolHistopathol., 2000, 15(1): 167-72). Accordingly, in some embodiments,the present invention provides a method of treating ulcerative colitis,in a patient in need thereof, comprising the step of administering tosaid patient a provided compound or a pharmaceutically acceptable saltthereof.

In some embodiments, the method of modulating TCR-Nck is used to treatuveitis. (See, e.g., Horai, R. et al., Immunity, 2015, 43(2): 343-53).Accordingly, in some embodiments, the present invention provides amethod of treating uveitis, in a patient in need thereof, comprising thestep of administering to said patient a provided compound or apharmaceutically acceptable salt thereof.

In some embodiments, the method of modulating TCR-Nck is used to treatvitiligo. (See, e.g., Van den Wijngaard, R. et al., Lab Invest. 2000,80(8): 1299-309). Accordingly, in some embodiments, the presentinvention provides a method of treating vitiligo, in a patient in needthereof, comprising the step of administering to said patient a providedcompound or a pharmaceutically acceptable salt thereof.

In some embodiments, the method of modulating TCR-Nck is used to treatrejection of transplants. (See, e.g., Issa, F. et al., Expert Rev. Clin.Immunol. 2010, 6(1): 155-69). Accordingly, in some embodiments, thepresent invention provides a method of treating rejection oftransplants, in a patient in need thereof, comprising the step ofadministering to said patient a provided compound or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the method of modulating TCR-Nck is used to treatgranulomatosis with polyangiitis (Wegener's granulomatosis). (See, e.g.,Morgan, M. D. et al., Arthritis & Rheumatism, 2011, 63(7): 2127-37).Accordingly, in some embodiments, the present invention provides amethod of treating granulomatosis with polyangiitis (Wegener'sgranulomatosis), in a patient in need thereof, comprising the step ofadministering to said patient a provided compound or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the method of modulating TCR-Nck is used to treathematological cancer. Accordingly, in some embodiments, the presentinvention provides a method of treating hematological cancer, in apatient in need thereof, comprising the step of administering to saidpatient a provided compound or a pharmaceutically acceptable saltthereof.

In some embodiments, the method of modulating TCR-Nck is used to treattransplant rejection. (See, e.g., Issa, F. et al., Expert Rev. Clin.Immunol. 2010, 6(1): 155-69). In some embodiments, the method ofmodulating TCR-Nck is used to treat graft-versus-host disease. (See,e.g., W. D., Nature Rev. Immunology, 2007, 7: 340-52). Accordingly, insome embodiments, the present invention provides a method of treating adisorder associated with transplantation, in a patient in need thereof,comprising the step of administering to said patient a provided compoundor a pharmaceutically acceptable salt thereof.

Autoimmune and Inflammatory Disorders

As used herein, “autoimmune and inflammatory disorder” refers to thosediseases, illnesses, or conditions engendered when the host's systemsare attacked by the host's own immune system. The targets of autoimmuneinteraction can range anywhere from the cellular level (e.g., myelinbasic protein in multiple sclerosis, or the thyrotropin receptor inGraves' disease) to organ specific effects in rheumatoid arthritis orCrohn's disease to system wide effects as seen in systemic lupuserythematosus. Some of the events that have been postulated in thecausation of autoimmune diseases have included cytokine over expression,for example TNF-α, IL-2, or IL-2 receptor in inflammatory bowel disease,or under expression (IL-10 under expression in Type 1 diabetes), todefects in allele expression (HLA Class I B27 in ankylosingspondylitis), to altered expression of apoptosis proteins (underexpression of Fas in autoimmune lymphoproliferative syndrome type I(ALPS 1). See “Harrison's Principles of Internal Medicine”, 16th ed.,McGraw-Hill, N. Y., 2005; Chapter 295 for additional information onautoimmune diseases.

In certain embodiments, the autoimmune or inflammatory disorder isAddison's disease, agammaglobulinemia, alopecia areata, alopeciauniversalis, amyloidosis, ankylosing spondylitis, anti-GBM/anti-TBMnephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmunedysautonomia, autoimmune encelphalomyelitis, autoimmune hepatitis,autoimmune inner ear disease (Meniere's disease), autoimmunemyocarditis, autoimmune pancreatitis, autoimmune retinopathy, autoimmuneurticarial, axon and neuronal neropathy, Baló disease, Behçet's disease,benign mucosal pemphigoid, bullous pemhigoid, Castleman disease, Celiacdisease, Chagasa disease, chronic inflammatory demyelinationpolyneuropathy, chronic recurrent multifocal osteomyelitis,Churg-Strauss, cicatrical pemphioid, Cogan's syndrome, cold agglutinindisease, congenital heart block, Coxsackie myocarditis, CREST syndrome,Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic'sdisease (neuromyelitis optica), discoid lupus, Dressler's syndrome,endometriosis, eosinophilic esophagitis, eosinophilic fasciitis,erythema nodosum, essential mixed cryoglobulinemia, Evan's syndrome,fibromyalgia, fibrosing alveolitis, giant cell arteritis, giant cellmyocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosiswith polyangitis, Grave's disease, Guillain-Barre Syndrome, Hashimoto'sthyroiditis, hemolytic anemia, Henoch-Schonlein purpura, herpesgestationis or pemphigoid gestationis, hypogammalglobulinemia, IgAnephropathy, IgG4-related sclerosing disease, immune thrombocytopenicpurpura, inclusion body myositis, inflammatory bowel disease,interstitial Eaton syndrome, leukocytoclasic vasculitis, lichen planus,lichen sclerosis, ligneous conjunctivitis, linear IgA disease, lupuserythematosus, Lyme disease chronic, Lyme neuroborreliosis, microscopicpolyangitis, mixed connective tissue disease, Mooren's ulcer,Mucha-Habermann disease, multiple sclerosis, myasthenia gravis,myositis, neuromyelitis optica, neutropenia, ocular cicatricialpemphigold, optic neuritis, palindromic rheumatism, PANDAS,paraneoplastic cerebellar degeneration, paroxysmal nocturnalhemoglobunuria, Parry-Romberg syndrome, Pars planitis, Parsonage-Turnersyndrome, pemphigus, peripheral neuropathy, perivenousencephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritisnodosa, polyglandular syndromes types I, II, and III, polymyalgiarhematica, polymyositis, postmyocardial infarction syndrome,postpericardiotomy syndrome, primary biliary cirrhosis, primarysclerosing cholangitis, progesterone dermatitis, psoriasis, psoriaticarthritis, pure red cell aplasia, pyoderma gangrenosum, Raynaud'sphenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsingpolychondritis, retroperitoneal fibrosis, rheumatic fever, rheumatoidarthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma,Sjogren's syndrome, sperm & testicular autoimmunity, stiff personsyndrome, subacute bacterial endocarditis (SBE), Susac's syndrome,sympathetic ophthalmia, Takayasu's arteritis, temporal arteritis,thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome, transversemyelitis, type 1 diabetes, ulcerative colitis, undifferentiatedconnective tissue disease, uveitis, vasculitis, vitiligo and Wegener'sgranulomatosis (or granulomatosis with polyangiitis).

Disorders Associated with Transplantation

In some embodiments, the disorder is associated with transplantation. Insome embodiments the disorder associated with transplantation istransplant rejection. In some embodiments the disorder associated withtransplantation is graft-versus-host disease.

Proliferative Disorders

In some embodiments, the disorder is a proliferative disorder. In someembodiments, the proliferative disorder is a cancer.

As used herein, the term “cancer” refers to cells having the capacityfor autonomous growth, i.e., an abnormal state or conditioncharacterized by rapidly proliferating cell growth. The term is meant toinclude all types of cancerous growths or oncogenic processes,metastatic tissues or malignantly transformed cells, tissues, or organs,irrespective of histopathologic type or stage of invasiveness. The term“tumor” as used herein refers to to malignancies of epithelial orendocrine tissues including respiratory system carcinomas,gastrointestinal system carcinomas, genitourinary system carcinomas,testicular carcinomas, breast carcinomas, prostatic carcinomas,endocrine system carcinomas, and melanomas. An “adenocarcinoma” refersto a carcinoma derived from glandular tissue or in which the tumor cellsform recognizable glandular structures. The term “sarcoma” is artrecognized and refers to malignant tumors of mesenchymal derivation.

Cancers include, without limitation, leukemias (e.g., acute leukemia,acute lymphocytic leukemia, acute myelocytic leukemia, acutemyeloblastic leukemia, acute promyelocytic leukemia, acutemyelomonocytic leukemia, acute monocytic leukemia, acuteerythroleukemia, chronic leukemia, chronic myelocytic leukemia, chroniclymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin'sdisease or non-Hodgkin's disease), Waldenstrom's macroglobulinemia,multiple myeloma, heavy chain disease, and solid tumors such as sarcomasand carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma,chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma,endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma,synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma,rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer,ovarian cancer, prostate cancer, squamous cell carcinoma, basal cellcarcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous glandcarcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterinecancer, testicular cancer, lung carcinoma, small cell lung carcinoma,bladder carcinoma, epithelial carcinoma, glioma, astrocytoma,medulloblastoma, craniopharyngioma, ependymoma, pinealoma,hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma,meningioma, melanoma, neuroblastoma, and retinoblastoma).

In some embodiments the proliferative disorder is a hematologicalcancers. In some embodiments the proliferative disorder is a leukemia.In some embodiments, the leukemia is a T-cell leukemia.

Neurological Disorders

In some embodiments, the disorder is a neurological disorder. In someembodiments, the neurological disorder is Balo's disease, chronicinflammatory demyelinating polyneuropathy, Devic's neuromyelitis optica,Marburg acute multiple sclerosis, multiple

Combinations

A compound of the current invention can be administered alone or incombination with one or more other therapeutic compounds, possiblecombination therapy taking the form of fixed combinations or theadministration of a compound of the invention and one or more othertherapeutic compounds being staggered or given independently of oneanother, or the combined administration of fixed combinations and one ormore other therapeutic compounds. As used herein, additional therapeuticagents that are normally administered to treat a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated.”

Those additional agents may be administered separately from an inventivecompound-containing composition, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a compound of thepresent invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form. Accordingly, the present inventionprovides a single unit dosage form comprising a compound of the currentinvention, an additional therapeutic agent, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.

The amount of both an inventive compound and additional therapeuticagent (in those compositions which comprise an additional therapeuticagent as described above) that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. Preferably,compositions of this invention should be formulated so that a dosage ofbetween 0.01-100 mg/kg body weight/day of an inventive compound can beadministered.

In those compositions which comprise an additional therapeutic agent,that additional therapeutic agent and the compound of this invention mayact synergistically. Therefore, the amount of additional therapeuticagent in such compositions will be less than that required in amonotherapy utilizing only that therapeutic agent. In such compositionsa dosage of between 0.01-1,000 μg/kg body weight/day of the additionaltherapeutic agent can be administered.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

In one embodiment, the present invention provides a compositioncomprising a compound of formula I and one or more additionaltherapeutic agents. The therapeutic agent may be administered togetherwith a compound of formula I, or may be administered prior to orfollowing administration of a compound of formula I. Suitabletherapeutic agents are described in further detail below. In certainembodiments, a compound of formula I may be administered up to 5minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours,12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hoursbefore the therapeutic agent. In other embodiments, a compound offormula I may be administered up to 5 minutes, 10 minutes, 15 minutes,30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14hours, 15 hours, 16 hours, 17 hours, or 18 hours following thetherapeutic agent.

In another embodiment, the present invention provides a method oftreating a TCR-Nck mediated disease, disorder or condition byadministering to a patient in need thereof a compound of formula I andone or more additional therapeutic agents. Such additional therapeuticagents may be small molecules or recombinant biologic agents andinclude, for example, acetaminophen, non-steroidal anti-inflammatorydrugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®)and celecoxib, colchicine (Colcrys®), corticosteroids such asprednisone, prednisolone, methylprednisolone, hydrocortisone, and thelike, probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine(Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) andchloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such asgold thioglucose (Solganal®), gold thiomalate (Myochrysine®) andauranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®),azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil(Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and“anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®),golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab(Humira®), “anti-IL-1” agents such as anakinra (Kineret®) and rilonacept(Arcalyst®), canakinumab (IIaris®), anti-Jak inhibitors such astofacitinib, antibodies such as rituximab (Rituxan®), “anti-T-cell”agents such as abatacept (Orencia®), “anti-IL-6” agents such astocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc®or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulantssuch as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®),antidiarrheals such as diphenoxylate (Lomotil®) and loperamide(Imodium®), bile acid binding agents such as cholestyramine, alosetron(Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk ofMagnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® andSenokot®, anticholinergics or antispasmodics such as dicyclomine(Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA,Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®),pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®),salmeterol xinafoate (Serevent®) and formoterol (Foradil®),anticholinergic agents such as ipratropium bromide (Atrovent®) andtiotropium (Spiriva®), inhaled corticosteroids such as beclomethasonedipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide(Azmacort®), mometasone (Asthmanex®), budesonide (Pulmicort®), andflunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium(Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®,Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such asomalizumab (Xolair®), nucleoside reverse transcriptase inhibitors suchas zidovudine (Retrovir®), abacavir (Ziagen®), abacavir/lamivudine(Epzicom®), abacavir/lamivudine/zidovudine (Trizivir®), didanosine(Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®),lamivudine/zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine(Hivid®), non-nucleoside reverse transcriptase inhibitors such asdelavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramune®)and etravirine (Intelence®), nucleotide reverse transcriptase inhibitorssuch as tenofovir (Viread®), protease inhibitors such as amprenavir(Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®),fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir(Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir(Fortovase®or Invirase®), and tipranavir (Aptivus®), entry inhibitorssuch as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integraseinhibitors such as raltegravir (Isentress®), doxorubicin(Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), anddexamethasone (Decadron R) in combination with lenalidomide (Revlimid®),or any combination(s) thereof.

In another embodiment, the present invention provides a method oftreating rheumatoid arthritis comprising administering to a patient inneed thereof a compound of formula I and one or more additionaltherapeutic agents selected from non-steroidal anti-inflammatory drugs(NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) andcelecoxib, corticosteroids such as prednisone, prednisolone,methylprednisolone, hydrocortisone, and the like, sulfasalazine(Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) andchloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such asgold thioglucose (Solganal®), gold thiomalate (Myochrysine®) andauranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®),azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil(Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and“anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®),golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab(Humira®), “anti-IL-1” agents such as anakinra (Kineret®) and rilonacept(Arcalyst®), antibodies such as rituximab (Rituxan®), “anti-T-cell”agents such as abatacept (Orencia®) and “anti-IL-6” agents such astocilizumab (Actemra®).

In some embodiments, the present invention provides a method of treatingosteoarthritis comprising administering to a patient in need thereof acompound of formula I and one or more additional therapeutic agentsselected from acetaminophen, non-steroidal anti-inflammatory drugs(NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) andcelecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®)and monoclonal antibodies such as tanezumab.

In some embodiments, the present invention provides a method of treatingsystemic lupus erythematosus comprising administering to a patient inneed thereof a compound of formula I and one or more additionaltherapeutic agents selected from acetaminophen, non-steroidalanti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen,etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone,prednisolone, methylprednisolone, hydrocortisone, and the like,antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine(Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®),azathioprine (Imuran®) and anticoagulants such as heparin (Calcinparine®or Liquaemin®) and warfarin (Coumadin®).

In some embodiments, the present invention provides a method of treatingCrohn's disease, ulcerative colitis, or inflammatory bowel diseasecomprising administering to a patient in need thereof a compound offormula I and one or more additional therapeutic agents diphenoxylate(Lomotil®) and loperamide (Imodium®), bile acid binding agents such ascholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®),laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®),Dulcolax®, Correctol® and Senokot® and anticholinergics orantispasmodics such as dicyclomine (Bentyl®), anti-TNF therapies,steroids, and antibiotics such as Flagyl or ciprofloxacin.

In some embodiments, the present invention provides a method of treatingasthma comprising administering to a patient in need thereof a compoundof formula I and one or more additional therapeutic agents selected fromSingulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil®HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterolacetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterolxinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agentssuch as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®),inhaled corticosteroids such as prednisone, prednisolone, beclomethasonedipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide(Azmacort®), mometasone (Asthmanex®), budesonide (Pulmicort®),flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®, cromolynsodium (Intal®), methylxanthines such as theophylline (Theo-Dur®,Theolair®, Uniphyl®, Theo-24®) and aminophylline, and IgE antibodiessuch as omalizumab (Xolair®).

In another embodiment, the present invention provides a method oftreating a hematological malignancy comprising administering to apatient in need thereof a compound of formula I and one or moreadditional therapeutic agents selected from rituximab (Rituxan®),cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®),vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, aBTK inhibitor, a JAK/pan-JAK inhibitor, a PI3K inhibitor, a SYKinhibitor, and combinations thereof.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a compound of formula I and a BTKinhibitor, wherein the disease is selected from inflammatory boweldisease, arthritis, systemic lupus erythematosus (SLE), vasculitis,idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis,psoriatic arthritis, osteoarthritis, Still's disease, juvenilearthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord'sthyroiditis, Graves' disease, autoimmune thyroiditis, Sjogren'ssyndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis,Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison'sdisease, opsoclonus-myoclonus syndrome, ankylosing spondylosis,antiphospholipid antibody syndrome, aplastic anemia, autoimmunehepatitis, thrombocytopenic purpura, optic neuritis, scleroderma,primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis,temporal arteritis, warm autoimmune hemolytic anemia, Wegener'sgranulomatosis, psoriasis, alopecia universalis, Behçet's disease,chronic fatigue, dysautonomia, membranous glomerulonephropathy,endometriosis, interstitial cystitis, pemphigus vulgaris, bullouspemphigoid, neuromyotonia, scleroderma, vulvodynia, a hyperproliferativedisease, rejection of transplanted organs or tissues, AcquiredImmunodeficiency Syndrome (AIDS, also known as HIV), type 1 diabetes,graft versus host disease, transplantation, transfusion, anaphylaxis,allergies (e.g., allergies to plant pollens, latex, drugs, foods, insectpoisons, animal hair, animal dander, dust mites, or cockroach calyx),type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, andatopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma,allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis,cholangitis, cholecystitis, chronic graft rejection, colitis,conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis,dermatomyositis, encephalitis, endocarditis, endometritis, enteritis,enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis,gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis,hidradenitis suppurativa, immunoglobulin A nephropathy, interstitiallung disease, laryngitis, mastitis, meningitis, myelitis myocarditis,myositis, nephritis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis,prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis,stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis,uveitis, vaginitis, vasculitis, or vulvitis, B-cell proliferativedisorder, e.g., diffuse large B cell lymphoma, follicular lymphoma,chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acutelymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacyticlymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma,multiple myeloma (also known as plasma cell myeloma), non-Hodgkin'slymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone Bcell lymphoma, nodal marginal zone B cell lymphoma, mantle celllymphoma, mediastinal (thymic) large B cell lymphoma, intravascularlarge B cell lymphoma, primary effusion lymphoma, Burkittlymphoma/leukemia, or lymphomatoid granulomatosis, breast cancer,prostate cancer, or cancer of the mast cells (e.g., mastocytoma, mastcell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer,colorectal cancer, pancreatic cancer, diseases of the bone and jointsincluding, without limitation, rheumatoid arthritis, seronegativespondyloarthropathies (including ankylosing spondylitis, psoriaticarthritis and Reiter's disease), Behçet's disease, Sjogren's syndrome,systemic sclerosis, osteoporosis, bone cancer, reocclusion afterangioplasty, restenosis after angioplasty, reocclusion afteraortocoronary bypass, restenosis after aortocoronary bypass, stroke,transitory ischemia, a peripheral arterial occlusive disorder, pulmonaryembolism, deep venous thrombosis), inflammatory pelvic disease,urethritis, skin sunburn, sinusitis, pneumonitis, encephalitis,meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis,gastritis, enteritis, dermatitis, gingivitis, appendicitis,pancreatitis, cholocystitus, agammaglobulinemia, psoriasis, allergy,Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren'sdisease, tissue graft rejection, hyperacute rejection of transplantedorgans, asthma, allergic rhinitis, chronic obstructive pulmonary disease(COPD), autoimmune polyglandular disease (also known as autoimmunepolyglandular syndrome), autoimmune alopecia, pernicious anemia,glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma,vasculitis, autoimmune hemolytic and thrombocytopenic states,Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson'sdisease, Alzheimer's disease, diabetes, septic shock, systemic lupuserythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenilearthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura,Waldenstrom macroglobulinemia, myasthenia gravis, Hashimoto'sthyroiditis, atopic dermatitis, degenerative joint disease, vitiligo,autoimmune hypopituitarism, Guillain-Barre syndrome, Behçet's disease,scleroderma, mycosis fungoides, acute inflammatory responses (such asacute respiratory distress syndrome and ischemia/reperfusion injury),and Graves' disease.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a compound of formula I and a PI3Kinhibitor, wherein the disease is selected from a cancer, aneurodegenerative disorder, an angiogenic disorder, a viral disease, anautoimmune disease, an inflammatory disorder, a hormone-related disease,conditions associated with organ transplantation, immunodeficiencydisorders, a destructive bone disorder, a proliferative disorder, aninfectious disease, a condition associated with cell death,thrombin-induced platelet aggregation, chronic myelogenous leukemia(CML), chronic lymphocytic leukemia (CLL), liver disease, pathologicimmune conditions involving T-cell activation, a cardiovasculardisorder, and a CNS disorder.

In some embodiments the present invention provides a method of treatingor lessening the severity of a disease comprising administering to apatient in need thereof a compound of formula I and a Bcl-2 inhibitor,wherein the disease is an inflammatory disorder, an autoimmune disorder,a proliferative disorder, an endocrine disorder, a neurological

A compound of the current invention may also be used to advantage incombination with antiproliferative compounds. Such antiproliferativecompounds include, but are not limited to aromatase inhibitors;antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors;microtubule active compounds; alkylating compounds; histone deacetylaseinhibitors; compounds which induce cell differentiation processes;cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors;antineoplastic antimetabolites; platin compounds; compoundstargeting/decreasing a protein or lipid kinase activity and furtheranti-angiogenic compounds; compounds which target, decrease or inhibitthe activity of a protein or lipid phosphatase; gonadorelin agonists;anti-androgens; methionine aminopeptidase inhibitors; matrixmetalloproteinase inhibitors; bisphosphonates; biological responsemodifiers; antiproliferative antibodies; heparanase inhibitors;inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasomeinhibitors; compounds used in the treatment of hematologic malignancies;compounds which target, decrease or inhibit the activity of Flt-3; Hsp90inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507),17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin,NSC707545), IPI-504, CNF 1010, CNF2024, CNF1010 from ConformaTherapeutics; temozolomide (Temodal®); kinesin spindle proteininhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, orpentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such asARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 fromPfizer and leucovorin. The term “aromatase inhibitor” as used hereinrelates to a compound which inhibits estrogen production, for instance,the conversion of the substrates androstenedione and testosterone toestrone and estradiol, respectively. The term includes, but is notlimited to steroids, especially atamestane, exemestane and formestaneand, in particular, non-steroids, especially aminoglutethimide,roglethimide, pyridoglutethimide, trilostane, testolactone,ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestaneis marketed under the trade name Aromasin™. Formestane is marketed underthe trade name Lentaron™. Fadrozole is marketed under the trade nameAfema™. Anastrozole is marketed under the trade name Arimidex™ Letrozoleis marketed under the trade names Femara™ or Femar™. Aminoglutethimideis marketed under the trade name Orimeten™. A combination of theinvention comprising a chemotherapeutic agent which is an aromataseinhibitor is particularly useful for the treatment of hormone receptorpositive tumors, such as breast tumors.

The term “antiestrogen” as used herein relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to the trade name Nolvadex™.Raloxifene hydrochloride is marketed under the trade name Evista™.Fulvestrant can be administered under the trade name Faslodex™.

The term “anti-androgen” as used herein relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide (Casodex™). The term“gonadorelin agonist” as used herein includes, but is not limited toabarelix, goserelin and goserelin acetate. Goserelin can be administeredunder the trade name Zoladex™.

The term “topoisomerase I inhibitor” as used herein includes, but is notlimited to topotecan, gimatecan, irinotecan, camptothecian and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148. Irinotecan can be administered, e.g., in the formas it is marketed, e.g., under the trademark Camptosar™. Topotecan ismarketed under the trade name Hycamptin™.

The term “topoisomerase II inhibitor” as used herein includes, but isnot limited to the anthracyclines such as doxorubicin (includingliposomal formulation, such as Caelyx™) daunorubicin, epirubicin,idarubicin and nemorubicin, the anthraquinones mitoxantrone andlosoxantrone, and the podophillotoxines etoposide and teniposide.Etoposide is marketed under the trade name EtopophosTM. Teniposide ismarketed under the trade name VM 26-Bristol Doxorubicin is marketedunder the trade name Acriblastin™ or Adriamycin™. Epirubicin is marketedunder the trade name Farmorubicin™. Idarubicin is marketed under thetrade name Zavedos™. Mitoxantrone is marketed under the trade nameNovantron.

The term “microtubule active agent” relates to microtubule stabilizing,microtubule destabilizing compounds and microtublin polymerizationinhibitors including, but not limited to taxanes, such as paclitaxel anddocetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate,vincristine or vincristine sulfate, and vinorelbine; discodermolides;cochicine and epothilones and derivatives thereof. Paclitaxel ismarketed under the trade name Taxol™. Docetaxel is marketed under thetrade name Taxotere™. Vinblastine sulfate is marketed under the tradename Vinblastin R.P™. Vincristine sulfate is marketed under the tradename Farmistin1υ.

The term “alkylating agent” as used herein includes, but is not limitedto, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU orGliadel). Cyclophosphamide is marketed under the trade name Cyclostin™.Ifosfamide is marketed under the trade name Holoxan™.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relatesto compounds which inhibit the histone deacetylase and which possessantiproliferative activity. This includes, but is not limited to,suberoylanilide hydroxamic acid (SAHA).

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylatingcompounds, such as 5-azacytidine and decitabine, methotrexate andedatrexate, and folic acid antagonists such as pemetrexed. Capecitabineis marketed under the trade name Xeloda™. Gemcitabine is marketed underthe trade name Gemzar™.

The term “platin compound” as used herein includes, but is not limitedto, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatincan be administered, e.g., in the form as it is marketed, e.g., underthe trademark Carboplat™. Oxaliplatin can be administered, e.g., in theform as it is marketed, e.g., under the trademark Eloxatin™.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity; or a protein or lipid phosphatase activity; or furtheranti-angiogenic compounds” as used herein includes, but is not limitedto, protein tyrosine kinase and/or serine and/or threonine kinaseinhibitors or lipid kinase inhibitors, such as a) compounds targeting,decreasing or inhibiting the activity of the platelet-derived growthfactor-receptors (PDGFR), such as compounds which target, decrease orinhibit the activity of PDGFR, especially compounds which inhibit thePDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, suchas imatinib, SU101, SU6668 and GFB-111; b) compounds targeting,decreasing or inhibiting the activity of the fibroblast growthfactor-receptors (FGFR); c) compounds targeting, decreasing orinhibiting the activity of the insulin-like growth factor receptor I(IGF-IR), such as compounds which target, decrease or inhibit theactivity of IGF-IR, especially compounds which inhibit the kinaseactivity of IGF-I receptor, or antibodies that target the extracellulardomain of IGF-I receptor or its growth factors; d) compounds targeting,decreasing or inhibiting the activity of the Trk receptor tyrosinekinase family, or ephrin B4 inhibitors; e) compounds targeting,decreasing or inhibiting the activity of the A×I receptor tyrosinekinase family; f) compounds targeting, decreasing or inhibiting theactivity of the Ret receptor tyrosine kinase; g) compounds targeting,decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosinekinase, such as imatinib; h) compounds targeting, decreasing orinhibiting the activity of the C-kit receptor tyrosine kinases, whichare part of the PDGFR family, such as compounds which target, decreaseor inhibit the activity of the c-Kit receptor tyrosine kinase family,especially compounds which inhibit the c-Kit receptor, such as imatinib;i) compounds targeting, (e.g., BCR-Ab1 kinase) and mutants, such ascompounds which target decrease or inhibit the activity of c-Ab1 familymembers and their gene fusion products, such as anN-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib(AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; ordasatinib (BMS-354825); j) compounds targeting, decreasing or inhibitingthe activity of members of the protein kinase C (PKC) and Raf family ofserine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK,PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC family, and/ormembers of the cyclin-dependent kinase family (CDK) includingstaurosporine derivatives, such as midostaurin; examples of furthercompounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1,Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521;LY333531/LY379196; isochinoline compounds; FTIs; PD184352 or QAN697 (aP13K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting,decreasing or inhibiting the activity of protein-tyrosine kinaseinhibitors, such as compounds which target, decrease or inhibit theactivity of protein-tyrosine kinase inhibitors include imatinib mesylate(Gleevec™) or tyrphostin such as Tyrphostin A23/RG-50810; AG 99;Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; TyrphostinB44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494;Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin); 1) compounds targeting, decreasing orinhibiting the activity of the epidermal growth factor family ofreceptor tyrosine kinases (EGFR₁ ErbB2, ErbB3, ErbB4 as homo- orheterodimers) and their mutants, such as compounds which target,decrease or inhibit the activity of the epidermal growth factor receptorfamily are especially compounds, proteins or antibodies which inhibitmembers of the EGF receptor tyrosine kinase family, such as EGFreceptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands,CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab(Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1,E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting,decreasing or inhibiting the activity of the c-Met receptor, such ascompounds which target, decrease or inhibit the activity of c-Met,especially compounds which inhibit the kinase activity of c-Metreceptor, or antibodies that target the extracellular domain of c-Met orbind to HGF, n) compounds targeting, decreasing or inhibiting the kinaseactivity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/orpan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib,pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and(PI3K) including but not limited to ATU-027, SF-1126, DS-7423,PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502,BYL-719, dactolisib, XL-147, XL-765, and idelalisib; and; and q)compounds targeting, decreasing or inhibiting the signaling effects ofhedgehog protein (Hh) or smoothened receptor (SMO) pathways, includingbut not limited to cyclopamine, vismodegib, itraconazole, erismodegib,and IPI-926 (saridegib).

The term “PI3K inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against one or more enzymes in thephosphatidylinositol-3-kinase family, including, but not limited toPI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α,p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87.Examples of PI3K inhibitors useful in this invention include but are notlimited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474,buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147,XL-765, and idelalisib.

The term “Bc1-2 inhibitor” as used herein includes, but is not limitedto compounds having inhibitory activity against B-cell lymphoma 2protein (Bc1-2), including but not limited to ABT-199, ABT-731, ABT-737,apogossypol, Ascenta's pan-Bc1-2 inhibitors, curcumin (and analogsthereof), dual Bc1-2/Bc1-xL inhibitors (InfinityPharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1(and analogs thereof; see WO2008118802), navitoclax (and analogsthereof, see U.S. Pat. No. 7,390,799), NH-1 (Shenayng PharmaceuticalUniversity), obatoclax (and analogs thereof, see WO2004106328), S-001(Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), andvenetoclax. In some embodiments the Bc2-2 inhibitor is a small moleculetherapeutic. In some embodiments the Bc2-2 inhibitor is apeptidomimetic.

The term “BTK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against Bruton's Tyrosine Kinase(BTK), including, but not limited to AVL-292 and ibrutinib.

The term “SYK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against spleen tyrosine kinase(SYK), including but not limited to PRT-062070, R-343, R-333, Excellair,PRT-062607, and fostamatinib

Further examples of BTK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2008039218 and WO2011090760, the entirety of which areincorporated herein by reference.

Further examples of SYK inhibitory compounds, and conditions treatableby WO2003063794, WO2005007623, and WO2006078846, the entirety of whichare incorporated herein by reference.

Further examples of PI3K inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2004019973, WO2004089925, WO2007016176, U.S. Pat. No.8,138,347, WO2002088112, WO2007084786, WO2007129161, WO2006122806,WO2005113554, and WO2007044729 the entirety of which are incorporatedherein by reference.

Further examples of JAK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2009114512, WO2008109943, WO2007053452, WO2000142246, andWO2007070514, the entirety of which are incorporated herein byreference.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity, e.g., unrelated to protein or lipid kinaseinhibition e.g., thalidomide (Thalomid™) and TNP-470.

Examples of proteasome inhibitors useful for use in combination withcompounds of the invention include, but are not limited to bortezomib,disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A,carfilzomib, ONX-0912, CEP-18770, and MLN9708.

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are e.g., inhibitors of phosphatase 1, phosphatase 2A,or CDC25, such as okadaic acid or a derivative thereof.

Compounds which induce cell differentiation processes include, but arenot limited to, retinoic acid, α- γ- or δ-tocopherol or α- γ- orδ-tocotrienol.

The term cyclooxygenase inhibitor as used herein includes, but is notlimited to, Cox-2 inhibitors, 5-alkyl substituted2-arylaminophenylacetic acid and derivatives, such as celecoxib(Celebrex™), rofecoxib (Vioxx™, etoricoxib, valdecoxib or a5-alkyl-2-arylaminophenylacetic acid, such as5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.

The term “bisphosphonates” as used herein includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid. Etridonic acid is marketedunder the trade name Didronel™. Clodronic acid is marketed under thetrade name Bonefos™. Tiludronic acid is marketed under the trade nameSkelid™ Pamidronic acid is marketed under the trade name Aredia™.Alendronic acid is marketed under Risedronic acid is marketed under thetrade name Actonel™. Zoledronic acid is marketed under the trade nameZometa™. The term “mTOR inhibitors” relates to compounds which inhibitthe mammalian target of rapamycin (mTOR) and which possessantiproliferative activity such as sirolimus (Rapamune®), everolimus(Certican™), CCI-779 and ABT578.

The term “heparanase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit heparin sulfate degradation. The termincludes, but is not limited to, PI-88. The term “biological responsemodifier” as used herein refers to a lymphokine or interferons.

The term “inhibitor of Ras oncogenic isoforms”, such as H-Ras, K-Ras, orN-Ras, as used herein refers to compounds which target, decrease orinhibit the oncogenic activity of Ras; for example, a “farnesyltransferase inhibitor” such as L-744832, DK8G557 or R115777(Zarnestra™). The term “telomerase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of telomerase.Compounds which target, decrease or inhibit the activity of telomeraseare especially compounds which inhibit the telomerase receptor, such astelomestatin.

The term “methionine aminopeptidase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of methionineaminopeptidase. Compounds which target, decrease or inhibit the activityof methionine aminopeptidase include, but are not limited to, bengamideor a derivative thereof.

The term “proteasome inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of the proteasome. Compoundswhich target, decrease or inhibit the activity of the proteasomeinclude, but are not limited to, Bortezomib (Velcade™) and MLN 341.

The term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) asused herein includes, but is not limited to, collagen peptidomimetic andnonpeptidomimetic inhibitors, tetracycline derivatives, e.g.,hydroxamate peptidomimetic inhibitor batimastat and its orallybioavailable analogue marimastat (BB-2516), prinomastat (AG3340),metastat (NSC 683551) BMS-279251 , BAY 12-9566, TAA211 , MMI270B orAAJ996.

The term “compounds used in the treatment of hematologic malignancies”as used herein includes, but is not limited to, FMS-like tyrosine kinaseinhibitors, which are compounds targeting, decreasing or inhibiting theactivity of FMS-like tyrosine kinase receptors (Flt-3R); interferon,1-β-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors,which are compounds which target, decrease or inhibit anaplasticlymphoma kinase.

Compounds which target, decrease or inhibit the activity of FMS-liketyrosine kinase receptors (Flt-3R) are especially compounds, proteins orantibodies which inhibit members of the Flt03R receptor kinase family,such as PKC412, midostaurin, a staurosporine derivative, SU11248 andMLN518.

The term “HSP90 inhibitors” as used herein includes, but is not limitedto, compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90; degrading, targeting, decreasing or inhibiting theHSP90 client proteins via the ubiquitin proteosome pathway. Compoundstargeting, decreasing or inhibiting the intrinsic ATPase activity ofHSP90 are especially compounds, proteins or antibodies which inhibit theATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin(17AAG), a geldanamycin derivative; other geldanamycin relatedcompounds; radicicol and HDAC inhibitors.

The term “antiproliferative antibodies” as used herein includes, but isnot limited to, trastuzumab (Herceptin™), Trastuzumab-DM1, erbitux,bevacizumab (Avastin™) rituximab (Rituxan®), PRO64553 (anti-CD40) and2C4 Antibody. By antibodies is meant intact monoclonal antibodies,polyclonal antibodies, multispecific antibodies formed from at least 2intact antibodies, and antibodies fragments so long as they exhibit thedesired biological activity.

For the treatment of acute myeloid leukemia (AML), compounds of thecurrent invention can be used in combination with standard leukemiatherapies, especially in combination with therapies used for thetreatment of AML. In particular, compounds of the current invention canbe administered in combination with, for example, farnesyl transferaseinhibitors and/or other drugs useful for the treatment of AML, such asDaunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone,Idarubicin, Carboplatinum and PKC412.

Other anti-leukemic compounds include, for example, Ara-C, a pyrimidineanalog, which is the 2′-alpha-hydroxy ribose (arabinoside) derivative ofdeoxycytidine. Also included is the purine analog of hypoxanthine,6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds whichtarget, decrease or inhibit activity of histone deacetylase (HDAC)inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid(SAHA) inhibit the activity of the enzymes known as histonedeacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228(formerly FR901228), Trichostatin A and compounds disclosed in U.S. Pat.No. 6,552,065 including, but not limited to,N-hydroxy-3-[4-[[[2-(2-methyl-1H-.indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or apharmaceutically acceptable salt thereof andN-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof, especially the lactatesalt. Somatostatin receptor antagonists as used herein refer tocompounds which target, treat or inhibit the somatostatin receptor suchas octreotide, and SOM230. Tumor cell damaging approaches refer toapproaches such as ionizing radiation. The term “ionizing radiation”referred to above and hereinafter means ionizing radiation that occursas either electromagnetic rays (such as X-rays and gamma rays) orparticles (such as alpha and beta particles). Ionizing radiation isprovided in, but not limited to, radiation therapy and is known in theart. See Hellman, “Principles of Radiation Therapy”, Cancer, inPrinciples and Practice of Oncology”, Devita et al., Eds., 4th Edition,Vol. 1, pp. 248-275 (1993).

Also included are EDG binders and ribonucleotide reductase inhibitors.The term “EDG binders” as used herein refers to a class ofimmunosuppressants that modulates lymphocyte recirculation, such asFTY720. The term “ribonucleotide reductase inhibitors” refers topyrimidine or purine nucleoside analogs including, but not limited to,fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine,5-fluorouracil, cladribine, 6-mercaptopurine (especially in combinationwith ara-C against ALL) and/or pentostatin. Ribonucleotide reductaseinhibitors are especially hydroxyurea or2-hydroxy-1H-isoindole-1,3-dione derivatives.

Also included are in particular those compounds, proteins or monoclonalantibodies of VEGF such as1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceuticallyacceptable salt thereof,1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate;Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; ZD6474;SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGFreceptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such asMacugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody,Angiozyme (RPI 4610) and Bevacizumab (Avastin™).

Photodynamic therapy as used herein refers to therapy which uses certainchemicals known as photosensitizing compounds to treat or preventcancers. Examples of photodynamic therapy include treatment withcompounds, such as Visudyne™ and porfimer sodium.

Angiostatic steroids as used herein refers to compounds which block orinhibit angiogenesis, such as, e.g., anecortave, triamcinolone,hydrocortisone, 11-α-epihydrocotisol, cortexolone,17α-hydroxyprogesterone, corticosterone, desoxycorticosterone,testosterone, estrone and dexamethasone.

Implants containing corticosteroids refers to compounds, such asfluocinolone and dexamethasone.

Other chemotherapeutic compounds include, but are not limited to, plantalkaloids, hormonal compounds and antagonists; biological responsemodifiers, preferably lymphokines or interferons; antisenseoligonucleotides or oligonucleotide derivatives; shRNA or siRNA; ormiscellaneous compounds or compounds with other or unknown mechanism ofaction.

The structure of the active compounds identified by code numbers,generic or trade names may be taken from the actual edition of thestandard compendium “The Merck Index” or from databases, e.g., PatentsInternational (e.g., IMS World Publications).

A compound of the current invention may also be used in combination withknown therapeutic processes, for example, the administration of hormonesor radiation. In certain embodiments, a provided compound is used as aradiosensitizer, especially for the treatment of tumors which exhibitpoor sensitivity to radiotherapy.

The compounds of this invention, or pharmaceutical compositions thereof,may also be incorporated into compositions for coating an implantablemedical device, such as prostheses, artificial valves, vascular grafts,stents and catheters. Vascular stents, for example, have been used toovercome restenosis (re-narrowing of the vessel wall after injury).However, patients using stents or other implantable devices risk clotformation or platelet activation. These unwanted effects may beprevented or mitigated by pre-coating the device with a pharmaceuticallyacceptable composition comprising a kinase inhibitor. Implantabledevices coated with a compound of this invention are another embodimentof the present invention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the percentage T cell inhibition (% Inh) of compoundsIb-21, I-1, Ia-1, Ia-3, Ib-17, Ia-2, Ib-18, Ib-19, Ib-4, Ib-8, Ib-23,Ib-24, Ib-26, Ib-28 and Ib-22, at a concentration of 0.1 nm.

FIG. 2 shows the percentage T cell inhibition (% Inh) of compounds Ib-1and Ib-20, at a concentration of 1.0 nM.

EXAMPLES Example 1. Synthesis of the Compounds of the Invention

General: The compounds of this invention may be prepared by means of theprocesses described below. In order to facilitate the description of theprocesses, we have used specific examples, which do not in any way limitthe scope of the present invention.

The starting reagents, solvents and products were acquired fromcommercial sources. The term “concentration” refers to vacuumevaporation using a BUchi rotary evaporator. When specified, thereaction products were purified by means of silica gel flashchromatography (40-63 microns) using the specified solvent system. Thespectroscopic data were measured using a Varian Mercury 400spectrometer. The melting points were measured using a BUchi 535instrument. The HPLC-MS was performed using a Gilson instrument equippedwith a Gilson 321 piston pump, a Gilson 864 vacuum degasser, a Gilson189 injection module, a Gilson 1/1000 splitter, a Gilson 307 pump, aGilson 170 detector, and a ThermoQuest Finnigan AQA detector.

Synthesis of compounds: Ib-1 to Ib-16

Step 1: Diethyl carbonate (37.8 g, 0.319 mol) was added drop wise to asuspension of NaH (60% dispersion in mineral oil, 18.0 g, 0.45 mol) indry toluene (250 ml) at r.t. (room temperature), under N₂. Afteraddition of methanol (3-5 drops), the mixture was heated to reflux and asolution of N-benzyl-4-piperidone 1 (30.0 g, 0.158 mol) in dry toluenewas added drop wise over 30 min. After evolution of H₂ is stopped (after2.5 h), reaction mixture was cooled to r.t., stirred for additional 2 hand acidified by adding AcOH (pH=4-5). The reaction mixture was furtherdiluted with ice-cold water (150 ml) and basified to pH=8 using aq. NH₃.The organic layer was separated and aqueous layer was re-extracted intoluene (3×100 ml). Combined organic extract was dried over anhydrousNa₂SO₄ and concentrated to result in crude mixture, which was purifiedby FCC (SiO₂: EtOAc/Hexane mixtures) to afford compound 2 (24.8 g, 60%yield) as yellow oil (Khartulyari et al., Eur. J. Org. Chem., 2007, 2,317324).

Step 2: Aniline (3.56 g, 0.038 mol) was added to a solution of compound2 (10.0 g, 0.038 mol) and glacial acetic acid (20 ml) in toluene (100ml) and whole reaction mixture was heated under N₂ atmosphere at 130° C.for 3 h (Note: Dean-Stark's apparatus connected). Reaction mixture wascooled to r.t. and concentrated on rotavapor to result in crudecompound, which was purified by column chromatography (Al₂O₃ activebasic, Hexanes) to afford compound 3 (6.4 g, 50% yield) as pale yellowliquid (Coscia et al., J. Am. Chem. Soc., 1959, 81, 3098-3100).

Step 3: A solution of compound 3 (4.4 g, 0.013 mol) and diphenyl ether(30 ml) was heated to 245° C. for 10-15 min (Note: Dean-Stark'sapparatus connected). Reaction mixture was gradually allowed to attainr.t. and diluted with hexane (220 ml). The resulting solid wastriturated with Et₂O:acetone (90 ml: 10 ml) and vacuum filtered toafford compound 4 (1.2 g, 32% yield) as pale yellow solid (Del et al.,J. Het. Chem., 1998, 35, 915-922).

Step 4: 10% Pd/C (45 mg, 15% w/w), 20% Pd(OH)₂ (45 mg, 15% w/w) andammonium formate (978 mg, 15.45 mmol) were added to a solution ofcompound 4 (300 mg, 1.03 mmol) in ethanol (5 ml), and entire reactionwas heated to 50° C. After 30 min, reaction mixture was cooled to r.t.;filtered over celite and washed with ethanol (10 ml). The filtrate wasconcentrated on rotavapor to afford crude compound 5 (150 mg) asoff-white solid which was taken to next step without furtherpurification (Li et al., Syn. Comm., 2006. 36, 925-928).

Step 5: 3-Methylbenzyl bromide (110 mg, 0.61 mmol) was added to asolution of compound 5 (150 mg, 0.75 mmol) and DIPEA(N,N-Diisopropylethylamine) (145 mg, 1.125 mmol) in acetonitrile (10ml), and reaction mixture was stirred at r.t. for 10 min. ReactionCombined organic extract was dried over anhydrous Na₂SO₄ andconcentrated on rotavapor to result in crude compound which was purifiedby prep. HPLC to afford compound Ib-2 (85 mg, 37% yield) as off-whitesolid. 1H NMR (DMSO-d6, 400 MHz): δ11.58 (br s, —NH), 8.02 (d, J=8.0 Hz,1H), 7.57 (t, J=8.0, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.25-7.14 (m, 4H),7.08 (d, J=7.6 Hz, 1H), 3.64 (s, 2H), 3.30 (s, 2H), 2.81 (m, 2H), 2.72(m, 2H), 2.31 (s, 3H). ES-MS [M+1]+: 305.1.

Synthesis of compounds: I-1, Ib-17 to Ib-19, and Ia-1 to Ia-3.

Step 1: Synthesis of Compound I-1

A solution of compound Ib-1 (500 mg, 1.72 mmol) in dry THF (20 ml) wasadded drop wise to a stirred suspension of NaH (60% dispersion inmineral oil, 138 mg, 3.45 mmol) in THF (20 ml) at 0° C., and stirred for10 min. Methyl iodide (267 mg, 2.5 mmol) was added and entire reactionmixture was stirred at r.t for 6 h. Reaction mixture was quenched withice-cold water (100 ml) and extracted with EtOAc (3×50 ml). Combinedorganic extract was dried over anhydrous Na₂SO₄ and concentrated onrotavapor to afford compound I-1 (425 mg, 81% yield) as pale yellowsolid. 1H NMR (DMSO-d6, 400 MHz): δ8.16 (dd, J=8.0, 1.6 Hz, 1H), 7.77(d, J=8.8, 1H), 7.70 (dd, J=8.0, 7.2 Hz,1H), 7.38-7.26 (m, 6H), 3.72 (s,3H), 3.69 (s, 2H), 3.35 (s, 2H), 2.99 (dd, J=6.0, 5.2 Hz, 2H), 2.73 (t,J=6.0, 2H). ES-MS [M+1]+: 305.0.

Step 2: Synthesis of Compound Ia-1

A solution of compound I-1 (150 mg, 0.49 mmol) in dry THF (20 ml) 5 wasadded drop wise to a stirred suspension of LAH (365 mg, 9.86 mmol) inTHF (30 ml) and stirred at r.t. for 24 h. Reaction mixture was cooled to0° C.; quenched by drop wise addition of Sat. Na₂SO₄ solution (20 ml)and stirred for 30 min. The inorganic salts were filtered and thefiltrate was concentrated on rotavapor to result in a crude residuewhich was purified by prep. HPLC to 10 afford compound Ia-1 (50 mg, 33%yield) as pale yellow solid. 1H NMR (DMSO-d6, 400 MHz): δ7.35-7.25 (m,5H), 7.08-7.01 (m, 2H), 6.52 (m, 2H), 6.01 (br s, —OH), 4.60 (d, J=4.0Hz, 1H), 3.45 (s, 2H), 3.34 (m, 1H), 2.85 (s, 3H), 2.58 (m, 2H), 2.28(m, 1H), 2.18 (m, 1H), 1.97 (m, 1H), 1.76 (m, 1H). ES-MS [M+1]+: 309.1.

Step 2: Synthesis of Compound Ia-2

To a stirred suspension of compound Ib-17 (300 mg, 0.94 mmol) in1,4-dioxane (10.0 ml), LAH (0.7 g, 18.0 mol) was added at 100° C. andstirred the reaction mixture for 4 h at the same temperature. After thistime, reaction mixture was quenched with sodium sulfate solution (25 ml)and filtered. Organic layer was on rotavapor and purified prep HPLC toafford compound Ia-2 (080 mg, 25% yield) as pale green oily compound. 1HNMR (DMSO-d6, 400 MHz): δ7.35-7.01 (m, 5H), 6.99-6.58 (m, 2H), 6.56-6.50(m, 1H), 6.48-6.46 (m, 1H), 4.67 (s, 1H), 3.53 (s, 2H), 3.41-3.39 (m,2H), 3.29-3.25 (m, 2H), 2.67-2.60 (m, 2H). ES-MS [M+1]+: 304.9.

Step 3: Synthesis of Compound Ia-3

Dess-Martin periodinane (468 mg, 1.103 mmol) followed by water (11 mg,0.61 mmol) were added to a solution of compound Ia-1 (170 mg, 0.551mmol) in CH₂C₁₂ (30 ml) at 0° C. and stirred at same temperature for 1.5h. Reaction mixture was quenched with 1:1 mixture (50 ml) of Sat.Na₂S₂O₃ and Sat. NaHCO₃ at 0° C. and stirred for 30 min. Reactionmixture was diluted with ice-cold water (50 ml) and extracted with EtOAc(3×50 ml). Combined organic extract was dried over anhydrous Na2SO4 andconcentrated on rotavapor to result in crude compound, which waspurified by prep. HPLC to afford compound Ia-3 (45 mg, 27% yield) aspale yellow oil. 1H NMR (DMSO-d6, 400 MHz): δ7.72 (dd, J=8.0, 2.0 Hz,1H), 7.40 (dd, J=8.0, 7.6 Hz, 1H), 7.347.30 (m, 4H), 7.24 (m, 1H), 6.71(d, J=8.8, Hz, 1H), 6.67 (t, J=7.2 Hz, 1H), 3.59 (m, 2H), 3.44 (m, 2H),2.96 (s, 3H), 2.92 (m, 1H), 2.77 (m, 1H), 1.96 (m, 2H), 1.67 (m, 1H),1.53 (m, 1H). ES-MS [M+1]+: 307.1.

Alternative Synthesis of Ia-3

Step 3: Synthesis of Compound Ia-b 3

To a solution of LAH (186 mg, 4.9 mmol) in THF (5 ml) was successivelyadded AlCl₃ (218 mg, 1.6 mmol) at 0-5° C. After stirred for 5 min at0-5° C., compound -1(200 mg, 0.6 mmol) in THF (5 ml) was added andstirred for 30 min at room temperature. The reaction mixture was thenquenched by water (20 ml) followed by extracted with EtOAc (2×25 ml).Combined organic extract were washed with brine solution (25 ml), driedover anhydrous Na₂SO₄ and concentrated. The crude was purified by prepHPLC to afford compound Ia-3 (80 mg, 40% yield) as pale yellow oil. 1HNMR (DMSO-d6, 400 MHz): δ7.72 (dd, J=8.0, 2.0 Hz, 1H), 7.40 (dd, J=8.0,7.6 Hz, 1H), 7.34-7.30 (m, 4H), 7.24 (m, 1H), 6.71 (d, J=8.8, Hz, 1H),6.67 (t, J=7.2 Hz, 1H), 3.59 (m, 2H), 3.44 (m, 2H), 2.96 (s, 3H), 2.92(m, 1H), 2.77 (m, 1H), 1.96 (m, 2H), 1.67 (m, 1H), 1.53 (m, 1H). ES-MS[M+1]+: 307.1.

Synthesis of Compounds: Ib-20 to Ib-29

R₂ R₃ Compound # Methyl Methyl Ib-20 Methoxy Methoxy Ib-21 Fluoro FluoroIb-22 Chloro H Ib-23 Methyoxy H Ib-24 Methyl H Ib-25 Cyano H Ib-26 HChloro Ib-27 H Methyoxy Ib-28 H Methyl Ib-29

Step 1: Synthesis of Compound 6

3,4-Dimethoxy Aniline (1.17 g, 0.0076 mol) was added to a solution ofcompound 2 (2.0 g, 0.0076 mol) and glacial acetic acid (4 ml) in toluene(20 ml) and reaction connected). Reaction mixture was cooled to roomtemperature and concentrated on rotavapor to result in crude compound,which was purified by column chromatography (Al₂O₃ active basic,Hexanes) to afford compound 6 (1.0g, 33.33% yield) as pale yellowliquid.

Step 2: Synthesis of Compound Ib-21

A solution of compound 6 (1.0 g, 0.0025 mol) and diphenyl ether (5.0 ml)was heated to 245 ° C. for 10-15 min (Note: Dean-Stark's apparatusconnected). Reaction mixture was gradually allowed to attain roomtemperature solid precipitated out. Filtered the solid and washed withhexane (20 ml) to afford Ib-21 (70.0 mg, 7.9% yields) as pale yellowsolid. 1H NMR (DMSO-d6, 400 MHz): δ1.34 (s, 1H), 7.37-7.29 (m, 6H), 7.26(s, 1H), 3.8 (s, 3H), 3.7 (s, 3H), 3.68 (s, 2H), 3.13 (m, 2H), 2.77-2.70(m, 4H). ES-MS [M+1]+: 350.8.

Example 2. Activity

The effect of compounds Ib-1, Ib-21, I-1, Ia-1, Ib-20, Ia-3, Ib-17,Ia—2, Ib-18, Ib-19, Ib-4, Ib-8, Ib-23, Ib-24, Ib-26, Ib-28, and Ib-22,on the capacity of the TCR to induce T cells proliferation was evaluatedon primary T cells obtained from the blood of healthy human donors(PBMCs; peripheral blood mononuclear cells). The volunteers' PBMCs wereisolated by means of density gradient of venous blood using Ficoll-PaquePlus. The purified cells (NWT; Nylon Wood T cells) were labelled withcarboxyfluorescein succinimidyl ester (CFSE) in order to analyse thecell division capacity. The labelled cells were pre-incubated for 1 hourin the absence or presence of each of the above compounds at aconcentration of 0.1 and 1.0 nM. Subsequently, the TCR/CD3 complex wasstimulated using immobilised OKT3 (10 μg/mL) on flat-bottom P96 platesfrom Costar. The cells were cultured in triplicate at a density of0.2×10⁵ in 200 μl of full medium, and the proliferation was evaluated bymeans of flow cytometry after 5-7 days, by quantifying the fluorescenceof the CFSE. As the cells divided, they diluted the amount of labelincorporated into the daughter cells, which indicates the degree ofcells proliferation. The inhibitory capacity of the tested compounds ata concentration of 0.1 and 1.0 nM, is shown in FIGS. 1 and 2,respectively.

Example 3. CYP Inhibition

The effect of compounds I-1, Ia-1, and Ib-22 on Cytochromes P450 (CYP)inhibition was evaluated.

For each isozyme, microsomes-buffer-substrate mixture (MBS mix) isprepared is transferred to a 96-well reaction plate. An aliquot (1 μL)is spiked from corresponding wells of Test Item stock solution plate toreaction plate. The reaction plate is pre-incubated for 5 minutes at 37° C. Reaction is initiated by the addition of 20 μL of NADPH solution.Each experiment is performed in duplicate. Reaction plate is incubatedfor predetermined time at 37° C. and quenched using either 200 μL ofacetonitrile (for CYP2C9, CYP2D6, CYP2C19 and CYP3A4) or 200 μL of amixture of 70:30 1% formic acid:acetonitrile (for CYP1A2). The proteinconcentration, incubation time, substrate concentrations and metabolitemonitored for each CYP is given in the table below:

Experimental conditions Isozyme Protein (mg/mL) Metabolite CYP1A2 0.15Acetaminophen CYP2C9 0.15 4-hydroxy diclofenac CYP2C19 0.25 4′-hydroxymephenytoin CYP2D6 0.15 Dextrorphan CYP3A4 0.10 1-hydroxy midazolam 0.156-β-hydroxy testosterone

Certain CYP inhibition data is shown in Table 3, below. Class A: IC50≤5uM; Class B: 5 uM<IC50≤20 uM; Class C: 20 uM<IC50≤50 uM; Class D:IC50>50 uM.

TABLE 3 CYP Inhibition CYP IC50 uM Compound # CYP1A2 CYP2C9 CYP2C19CYP2D6 CYP3A4^(a) CYP3A4^(b) I-1 C D C A D D Ia-1 B N/A A A A CIb-22 >12.5 >12.5 B A >12.5 >12.5

Example 4. Microsomal Stability

The microsomal stability of compounds I-1, Ia-1, and Ib-22 wasevaluated.

Intrinsic clearance studies are performed individually with mouse, ratand human liver microsomes at 0.5 mg/mL protein concentration. Briefly,for protein concentration 0.5 mg/mL assay, liver microsomal protein(12.5 uL), NAPDH (50 uL) and phosphate buffer (435 uL) are co-incubated(pre-incubation) in a 96-well deep well plate in an orbital incubator(10 min, 37 ° C.). Reactions are initiated by the addition of 2.5 uL oftest item working stock solution (100 uM). Aliquots (50 uL) arewithdrawn from the reaction tube at 0, 5, 10, 20 and 30 minutes and thereaction is immediately terminated by transferring to a 96 deep wellplate containing 50 uL of acetonitrile Veranamil is used as a positivecontrol in mouse rat and human liver microsomes. To the quenched samplesinternal standard is added and vortex mixed followed by centrifugationat 4000 rpm for 10 minutes and an aliquot of supernatant is taken forLC-MS/MS analysis. Samples are analyzed by a suitable fit-for-purposemultiple reaction monitoring method developed on LC-MS/MS using and API4000 mass spectrometer to estimate the area ratio (analyte peakarea/internal standard peak area).

Certain microsomal stability data is shown in Table 4, below. Class A:T1/2≤30 minutes; Class B: 10 minutes≤T1/2<30 minutes; Class C: T1/2<10minutes.

TABLE 4 Microsomal Stability Microsomal stability (T½ min) Compound #Mouse Rat Human I-1 B B A Ia-1 C C B Ib-22 B B A

Example 5. hERG Inhibition

The effect of compounds I-1, Ia-1, and Ib-22 on hERG inhibition wasevaluated.

HEK cells stably transfected with the hERG clone are maintained at 37±2°C. in a 5% CO2 incubator. The cells are initially revived and grown inDMEM/F12+GlutaMAX-I medium supplemented with 9% fetal bovine serum (FBS)and antibiotics (Penicillin 100 IU/mL Streptomycin 100 μg/mL) (completemedium). Furthermore, the cells are continuously maintained and passagedin complete media in addition to the appropriate concentration ofselection antibiotic (Geneticin (G418) 200 μg/mL) (Selection media). Thecells are sub cultured every 2-3 days and medium is changed withcomplete medium at least a day before the experiment.

The cells are harvested on the day of experiment, dislodged andsuspended in sterile filtered external solution (NaCl 140 mM, KCl 4 mM,MgCl2 1 mM, CaCl2 2 mM, D-Glucose monohydrate 5 mM, Hepes/NaOH 10 mM, pH7.4, Osmolarity:298+/−5 mOsmol).

The NPC®-1 chip of the Port-a-Patch® is filled with 5 μL of internalsolution (KCl 50 mM, NaCl 10 mM, KFl 60 mM, EGTA 20 mM, Hepes/KOH 10 mM,pH 7.2, Osmolarity: 285+/−5 mOsmol) and it is screwed onto the chipholder. The Faraday cage is then fixed on the chip holder, such that theexternal electrode is placed near to the chip aperture. 5 uL of externalsolution is added to the center of the aperture so that the externalelectrode is also in contact with the solution.

The experiment is be initiated. Once the set threshold of resistanceattained (i.e., 2-3.5 MOhm), 5 μof cell suspension is added in themiddle of the external solution droplet after the Suction Control unithas generated the suction pulse. The suction automatically attracts acell to the aperture, resulting in an increase in the chip resistance.When the cell is captured and the set threshold for the resistance isreached, the software recognizes this increase in resistance andproceeds to the next step of the sealing procedure. 20 μl of sealenhancer solution (NaCl 80 mM, KCl4 mM, MgCl2 10 mM, CaCl2 35 mM, Hepes(Na+salt)/HCl pH 7.4, Osmolarity: 298+/−5 mOsmol) is added 2-3 times.When the threshold resistance is reached, Patch Control automaticallymoves to the step of improving the seal. When the desirable resistance(Rpip) is reached, whole cell mode is attained and maintained.

Finally, hERG protocol is selected to run the experiment. The sealenhancer solution is replaced with 20 μl external solution after 2-4rinses and then the test item is added (from lower to higherconcentration) and checked for current inhibition. All the experimentsare performed at ambient temperature (22-25° C.).

A schematic diagram of the Pulse protocol: Cells are stimulated every 10seconds using the following protocol. The holding potential, sweepintervals and the depolarization/repolarization potentials are furnishedin the table below.

Protocol Voltage (mili-volts) Duration (mili-seconds) Holding potential−80 51 Depolarization +40 500 Repolarization −40 500 Holding potential−80 200

Once the stable current is attained (at least 2-5 minutes) vehiclecontrol is added and the current measured till the stable current isachieved. 3-5 consecutive data points from the last stable current phaseare considered for further analysis. The test concentrations areanalyzed from the lower to the higher concentrations (1, 3, 10 and 30 μMin duplicates till stable current is achieved along with positivecontrol. The system performs on-line analysis for several parameterswhich include functions that acquire data from traces and functions thatperform calculations on the results of other functions.

Certain hERG inhibition data is shown in Table 5, below.

TABLE 5 hERG Inhibition Concentration Percent Inhibition Compound # (μM)Trial I Trial II Mean (%) Effect of I-1 on IKr current I-1 1 9.22 8.859.04 3 20.39 21.39 20.89 10 39.58 35.94 37.76 30 58.85 58.33 58.59Propafenone 10 82.82 88.54 85.68 IC 50 = 18.43 μM Effect of Ia-1 on IKrcurrent Ia-1 1 12.92 9.88 11.40 3 21.26 22.52 21.89 10 29.42 28.30 28.8630 54.76 54.10 54.43 Propafenone 10 64.80 76.53 70.67 IC 50 = 25.73 μMEffect of Ib-22 on IKr current Ib-22 1 5.62 3.37 4.50 3 15.99 14.6015.30 10 23.83 19.03 21.43 30 33.97 26.19 30.08 Propafenone 10 75.5068.27 71.89 IC 50 = 47.33 μM

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: ----- representsan optional double bond; each R₁ independently represents —H, —CN,halogen, —OR₄ or —C₁₋₄ alkyl; each R′₁ independently represents —H, —CN,halogen, —OR₄ or —C₁₋₄ alkyl; R₂ represents ═O or —OH; R₃ represents —H,—OR₄, —C₁₋₄ alkyl or C₁₋₄ alkyl-Cy; Cy represents a phenyl group, a 5-or 6-membered aromatic heterocycle containing 1 or 2 heteroatomsselected from O, N and S at any available position on the ring, whereinCy is optionally substituted with one or more R₄ groups; and each R₄group independently represents —H or —C₁₋₄ alkyl; with the conditionthat the compound of formula I is not2-benzyl-5-methyl-1,2,3,4-tetrahydro(5H,10H)-benzo(b)-1,6-naphthyridin-10-one.2. The compound, or the pharmaceutically acceptable salt thereof,according to claim 1, wherein R₃ represents —H, —C₁₋₄ alkyl or C₁₋₄alkyl-Cy.
 3. The compound, or the pharmaceutically acceptable saltthereof, according to claim 1, selected from a compound of formula Ia:

wherein: each R₁ independently represents —H, CN, halogen, —OR₄ or —C₁₋₄alkyl; each R′₁ independently represents —H, —CN, halogen, —OR₄ or —C₁₋₄alkyl; R₂ represents ═O or —OH; R₃ represents —H, —OR4, —C₁₋₄ alkyl or—C₁₋₄ alkyl-Cy; Cy represents a phenyl group, a 5- or 6-memberedaromatic heterocycle containing 1 or 2 heteroatoms selected from O, Nand S at any available position on the ring, wherein Cy is optionallysubstituted with one or more R₄ groups; and each R₄ group independentlyrepresents —H or —C₁₋₄ alkyl.
 4. The compound, or the pharmaceuticallyacceptable salt thereof, according to claim 3, wherein R₃ represents —H,—C₁₋₄ alkyl or C₁₋₄ alkyl-Cy.
 5. The compound, or the pharmaceuticallyacceptable salt thereof according to claim 1, selected from a compoundof formula Ib:

wherein: each R₁ independently represents —H, —CN, halogen, —OR₄ or—C₁₋₄ alkyl; each R′₁ independently represents —H, —CN, halogen, —OR₄ or—C₁₋₄ alkyl; R₂ represents ═O or —OH; R₃ represents —H, —OR₄, —C₁₋₄alkyl or —C₁₄ alkyl-Cy; Cy represents a phenyl group, a 5- or 6-memberedaromatic heterocycle containing 1 or 2 heteroatoms selected from O, Nand S at any available position on the ring, wherein Cy is optionallysubstituted with one or more independent R₄ groups; and each R₄ groupindependently represents —H or —C₁₋₄ alkyl; with the condition that thecompound of formula I is not2-benzyl-5-methyl-1,2,3,4-tetrahydro(5H,10H)-benzo(b)-1,6-naphthyridin-10-one.6. The compound, or the pharmaceutically acceptable salt thereof,according to claim 5, wherein R₃ represents —H, —C₁₋₄ alkyl or —C₁₋₄alkyl-Cy
 7. The compound, or the pharmaceutically acceptable saltthereof, according to any one of claims 1 to 6, wherein one R′₁represents —H, and the other R′₁ represents —H, —CN, halogen, —OC₁₋₄alkyl or C₁₋₄ alkyl.
 8. The compound, or the pharmaceutically acceptablesalt thereof, according to any one of claims 1 to 7, wherein one R₁represents —H, and the other R₁ represents —H, —CN, halogen, —OC₁₋₄alkyl or C₁₋₄ alkyl.
 9. The compound, or the pharmaceutically acceptablesalt thereof, according to any one of claims 1 to 8, wherein R₂represents ═O.
 10. The compound, or the pharmaceutically acceptable saltthereof, according to any one of claims 1 to 8, wherein R₂ represents—OH.
 11. The compound, or the pharmaceutically acceptable salt thereof,according to any one of claim 5 or 6, wherein R₁ and R′₁ represent —H,R₂ represents ═O, and R₃ represents C₂₋₄ alkyl.
 12. The compound, or thepharmaceutically acceptable salt thereof, according to claim 1, selectedfrom:


13. A pharmaceutical composition that comprises a compound, or apharmaceutically acceptable salt thereof, of any one of claims 1 to 12,and one or more pharmaceutically acceptable excipients.
 14. Thecompound, or the pharmaceutically acceptable salt thereof, of any one ofclaims 1 to 12, or the pharmaceutical composition of claim 13, for useas a medicament.
 15. The compound, or the pharmaceutically acceptablesalt thereof, or the pharmaceutical composition, for use as a medicamentaccording to claim 14, for the treatment and/or prevention of a diseaseassociated with an abnormal activation of T cells.
 16. The compound, orthe pharmaceutically acceptable salt thereof, or the pharmaceuticalcomposition, for use as a medicament according to claim 15, wherein thedisease associated with an abnormal activation of T cells is selectedfrom the group consisting of: an autoimmune disease, a mast-cellmediated allergy, a rejection of an allotransplant or a xenotransplantof an organ or a tissue, a lymphoma or a T-cell leukaemia.
 17. Thecompound, or the pharmaceutically acceptable salt thereof, or thepharmaceutical composition, for use as a medicament according to claim16, wherein the autoimmune disease is selected from the group consistingof: rheumatoid arthritis, vitiligo, autoimmune hepatitis, myastheniagravis, ankylosing spondylitis, inflammatory bowel disease, Crohn'sdisease, ulcerative colitis, psoriatic arthritis, transplant rejection,psoriasis, type I diabetes, multiple sclerosis, systemic lupuserythematosus, asthma, and atopic dermatitis.
 18. Process for preparinga compound of formula I, which comprises making1,2,3,4-tetrahydro-2-benzo[b][1,6]naphthyridin-10(5H)-one react withcorresponding substituted benzyl halides under basic conditions.
 19. Thecompound, or the pharmaceutically acceptable salt thereof, according toany one of claims 1-6, wherein R₃ represents —H.
 20. The compound, orthe pharmaceutically acceptable salt thereof, according to any one 21.The compound, or the pharmaceutically acceptable salt thereof, accordingto any one of claims 1-6, wherein R₃ represents methyl.
 22. Thecompound, or the pharmaceutically acceptable salt thereof, according toany one of claims 1-6, wherein R₃ represents ethyl.
 23. The compound, orthe pharmaceutically acceptable salt thereof, according to any one ofclaims 1-6, wherein R₃ represents isopropyl.
 24. The compound accordingto any one of claims 1-12, or the pharmaceutically acceptable saltthereof, selected from those depicted in Tables 1 and
 2. 25. Apharmaceutical composition that comprises a compound, or apharmaceutically acceptable salt thereof, of any one of claims 19 to 24,and one or more pharmaceutically acceptable excipients.
 26. Thecompound, or the pharmaceutically acceptable salt thereof, of any one ofclaims 19 to 24, or the pharmaceutical composition of claim 25, for useas a medicament for the treatment of a disease associated with anabnormal activation of T cells.
 27. The compound, or thepharmaceutically acceptable salt thereof, or the pharmaceuticalcomposition, for use as a medicament according to claim 26, wherein thedisease associated with an abnormal activation of T cells is selectedfrom the group consisting of: an autoimmune disease, a mast-cellmediated allergy, a rejection of an allotransplant or a xenotransplantof an organ or a tissue, a lymphoma or a T-cell leukaemia.
 28. Thecompound, or the pharmaceutically acceptable salt thereof, or thepharmaceutical composition, for use as a medicament according to claim27, wherein the autoimmune disease is selected from the group consistingof: rheumatoid arthritis, vitiligo, autoimmune hepatitis, myastheniagravis, ankylosing spondylitis, inflammatory bowel disease, Crohn'sdisease, ulcerative colitis, psoriatic arthritis, transplant rejection,psoriasis, type I diabetes, multiple sclerosis, systemic lupuserythematosus, asthma, and atopic dermatitis.
 29. A pharmaceuticalcomposition that comprises a compound:

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.
 30. The compound:

or a pharmaceutically acceptable salt thereof, for use as a medicamentfor treatment of a disease associated with an abnormal activation of Tcells.
 31. The compound, or the pharmaceutically acceptable saltthereof, for use according to claim 30, wherein the disease associatedwith an abnormal activation of T cells is selected from the groupconsisting of: an autoimmune disease, a mast-cell mediated allergy, arejection of an allotransplant or a xenotransplant of an organ or atissue, a lymphoma and a T-cell leukaemia.
 32. The compound, or thepharmaceutically acceptable salt thereof, for use according to claim 31,wherein the autoimmune disease is selected from the group consisting of:rheumatoid arthritis, vitiligo, autoimmune hepatitis, myasthenia gravis,ankylosing spondylitis, inflammatory bowel disease, Crohn's disease,ulcerative colitis, psoriatic arthritis, transplant rejection,psoriasis, type I diabetes, multiple sclerosis, systemic lupuserythematosus, asthma, uveitis and atopic dermatitis.
 33. A method forpreparing a compound of formula I, or a salt thereof, comprisingreacting

a compound of formula II: or a salt thereof, with a compound of formulaIII

or a salt thereof, wherein: LG is a leaving group; ----- represents anoptional double bond; each R₁ independently represents —H, —CN, halogen,—OR₄ or —C₁₋₄ alkyl; each R′₁ independently represents —H, —CN, halogen,—OR₄ or —C₁₋₄ alkyl; R₂ represents ═O or —OH; R₃ represents —H, —OR₄,—C₁₋₄ alkyl or C₁₋₄ alkyl-Cy; Cy represents a phenyl group, a 5- or6-membered aromatic heterocycle containing 1 or 2 heteroatoms selectedfrom O, N and S at any available position on the ring, wherein Cy isoptionally substituted with one or more R₄ groups; and each R₄ groupindependently represents —H or —C₁₋₄ alkyl.
 34. The method according toclaim 33, wherein the compound of formula I is not2-benzyl-5-methyl-1,2,3,4-tetrahydro(5H,10H)-benzo(b)-1,6-naphthyridin-10-one.